Publications by authors named "Damien Colas"

24 Publications

  • Page 1 of 1

Loss of Circadian Timing Disrupts Theta Episodes during Object Exploration.

Clocks Sleep 2020 Dec 1;2(4):523-535. Epub 2020 Dec 1.

Biology Department, Stanford University, Stanford, CA 94305, USA.

This study examined whether theta oscillations were compromised by the type of circadian disruption that impairs hippocampal-dependent memory processes. In prior studies on Siberian hamsters, we developed a one-time light treatment that eliminated circadian timing in the central pacemaker, the suprachiasmatic nucleus (SCN). These arrhythmic animals had impaired hippocampal-dependent memory whereas animals made arrhythmic with SCN lesions did not. The current study examined whether theta oscillations are compromised by the same light treatment that produced memory impairments in these animals. We found that both methods of inducing circadian-arrhythmia shortened theta episodes in the EEG by nearly 50%. SCN-lesioned animals, however, exhibited a 3-fold increase in the number of theta episodes and more than doubled the total time that theta dominated the EEG compared to SCN-intact circadian-arrhythmic animals. Video tracking showed that changes in theta were paralleled by similar changes in exploration behavior. These results suggest that the circadian-arrhythmic SCN interferes with hippocampal memory encoding by fragmenting theta oscillations. SCN-lesioned animals can, however, compensate for the shortened theta episodes by increasing their frequency. Implications for rhythm coherence and theta sequence models of memory formation are discussed.
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http://dx.doi.org/10.3390/clockssleep2040038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711584PMC
December 2020

Report on Electroencephalographic Findings in Critically Ill Patients with COVID-19.

Ann Neurol 2020 09 9;88(3):626-630. Epub 2020 Jul 9.

BioSerenity, Atlanta, GA.

In March 2020, we treated a cohort of 26 critically ill hospitalized SARS-CoV-2-infected patients who underwent electroencephalography to assess unexplained altered mental status, loss of consciousness, or poor arousal and responsiveness. Of the 26 patients studied, 5 patients had electroencephalograms that showed periodic discharges consisting of high-amplitude frontal monomorphic delta waves with absence of epileptic activity. These findings may suggest central nervous system injury potentially related to COVID-19 in these patients. ANN NEUROL 2020;88:626-630.
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http://dx.doi.org/10.1002/ana.25814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7323170PMC
September 2020

Suprachiasmatic lesions restore object recognition in down syndrome model mice.

Neurobiol Sleep Circadian Rhythms 2020 May 16;8:100049. Epub 2020 Feb 16.

Biology Department, 371 Serra Mall, Stanford University, Stanford, CA, 94305-5020, USA.

The Ts65Dn mouse is a well-studied model of trisomy 21, Down syndrome. This mouse strain has severe learning disability as measured by several rodent learning tests that depend on hippocampal spatial memory function. Hippocampal long-term potentiation (LTP) is deficient in these mice. Short-term daily treatment with low-dose GABA receptor antagonists rescue spatial learning and LTP in Ts65Dn mice leading to the hypothesis that the learning disability is due to GABAergic over-inhibition of hippocampal circuits. The fact that the GABA receptor antagonists were only effective if delivered during the daily light phase suggested that the source of the excess GABA was controlled directly or indirectly by the circadian system. The central circadian pacemaker of mammals is the suprachiasmatic nucleus (SCN), which is largely a GABAergic nucleus. In this study we investigated whether elimination of the SCN in Ts65Dn mice would restore their ability to form recognition memories as tested by the novel object recognition (NOR) task. Full, but not partial lesions of the SCN of Ts65Dn mice normalized their ability to perform on the NOR test. These results suggest that the circadian system modulates neuroplasticity over the time frame involved in the process of consolidation of recognition memories.
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http://dx.doi.org/10.1016/j.nbscr.2020.100049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7075983PMC
May 2020

Adaptive Accelerometry Derived Respiration: Comparison with Respiratory Inductance Plethysmography during Sleep.

Annu Int Conf IEEE Eng Med Biol Soc 2019 Jul;2019:6714-6717

Polysomnography (PSG) is a multi-parametric test used in the study of sleep and as a diagnostic tool in sleep medicine. PSG is the gold standard that manually quantifies the apnea-hypopnea index (AHI) to assess the severity of sleep apnea syndrome (SAS). This work presents a novel method based on a dual tri-axis accelerometer system (Adaptive Accelerometry Derived Respiration, ADR) which was patched on the subject's chest that adaptively reconstructed thoracic and abdominal respiratory efforts. Performance evaluation was performed on a 60s-epoch basis using signal and physiological indicators: the evaluation consisted in the comparison of airflow estimations from ADR and RIP to the nasal airflow, considered as reference. Results showed that 74% of the 60s-epoch ADR airflow estimation present a correlation coefficient with nasal airflow ≥ 70% compared to 64% for RIP. Relative errors for one-minute respiration rate and tidal volume estimation appeared to be relatively low which reflected the good feasibility of the adaptive ADR method for respiration monitoring during sleep.
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http://dx.doi.org/10.1109/EMBC.2019.8856561DOI Listing
July 2019

Short-term treatment with flumazenil restores long-term object memory in a mouse model of Down syndrome.

Neurobiol Learn Mem 2017 Apr 12;140:11-16. Epub 2017 Feb 12.

Biology Department, Stanford University, Stanford, CA 94305-5020, USA. Electronic address:

Down syndrome (DS) is a common genetic cause of intellectual disability yet no pro-cognitive drug therapies are approved for human use. Mechanistic studies in a mouse model of DS (Ts65Dn mice) demonstrate that impaired cognitive function is due to excessive neuronal inhibitory tone. These deficits are normalized by chronic, short-term low doses of GABA receptor (GABAR) antagonists in adult animals, but none of the compounds investigated are approved for human use. We explored the therapeutic potential of flumazenil (FLUM), a GABAR antagonist working at the benzodiazepine binding site that has FDA approval. Long-term memory was assessed by the Novel Object Recognition (NOR) testing in Ts65Dn mice after acute or short-term chronic treatment with FLUM. Short-term, low, chronic dose regimens of FLUM elicit long-lasting (>1week) normalization of cognitive function in both young and aged mice. FLUM at low dosages produces long lasting cognitive improvements and has the potential of fulfilling an unmet therapeutic need in DS.
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http://dx.doi.org/10.1016/j.nlm.2017.02.006DOI Listing
April 2017

Cyclooxygenase inhibition targets neurons to prevent early behavioural decline in Alzheimer's disease model mice.

Brain 2016 07 13;139(Pt 7):2063-81. Epub 2016 May 13.

1 Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA

Identifying preventive targets for Alzheimer's disease is a central challenge of modern medicine. Non-steroidal anti-inflammatory drugs, which inhibit the cyclooxygenase enzymes COX-1 and COX-2, reduce the risk of developing Alzheimer's disease in normal ageing populations. This preventive effect coincides with an extended preclinical phase that spans years to decades before onset of cognitive decline. In the brain, COX-2 is induced in neurons in response to excitatory synaptic activity and in glial cells in response to inflammation. To identify mechanisms underlying prevention of cognitive decline by anti-inflammatory drugs, we first identified an early object memory deficit in APPSwe-PS1ΔE9 mice that preceded previously identified spatial memory deficits in this model. We modelled prevention of this memory deficit with ibuprofen, and found that ibuprofen prevented memory impairment without producing any measurable changes in amyloid-β accumulation or glial inflammation. Instead, ibuprofen modulated hippocampal gene expression in pathways involved in neuronal plasticity and increased levels of norepinephrine and dopamine. The gene most highly downregulated by ibuprofen was neuronal tryptophan 2,3-dioxygenase (Tdo2), which encodes an enzyme that metabolizes tryptophan to kynurenine. TDO2 expression was increased by neuronal COX-2 activity, and overexpression of hippocampal TDO2 produced behavioural deficits. Moreover, pharmacological TDO2 inhibition prevented behavioural deficits in APPSwe-PS1ΔE9 mice. Taken together, these data demonstrate broad effects of cyclooxygenase inhibition on multiple neuronal pathways that counteract the neurotoxic effects of early accumulating amyloid-β oligomers.
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http://dx.doi.org/10.1093/brain/aww117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4939702PMC
July 2016

Sleep disruption impairs haematopoietic stem cell transplantation in mice.

Nat Commun 2015 Oct 14;6:8516. Epub 2015 Oct 14.

Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California 94305, USA.

Many of the factors affecting the success of haematopoietic cell transplantation are still unknown. Here we show in mice that donor sleep deprivation reduces the ability of its haematopoietic stem cells (HSCs) to engraft and reconstitute the blood and bone marrow of an irradiated recipient by more than 50%. We demonstrate that sleep deprivation downregulates the expression of microRNA (miR)-19b, a negative regulator of the suppressor of cytokine signalling (SOCS) genes, which inhibit HSC migration and homing. Accordingly, HSCs from sleep-deprived mice have higher levels of SOCS genes expression, lower migration capacity in vitro and reduced homing to the bone marrow in vivo. Recovery of sleep after sleep deprivation restored the reconstitution potential of the HSCs. Taken together, this study provides insights into cellular and molecular mechanisms underlying the effects of sleep deprivation on HSCs, emphasizing the potentially critical role of donor sleep in the success of bone marrow transplantation.
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http://dx.doi.org/10.1038/ncomms9516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4621781PMC
October 2015

Loss of Melanopsin Photoreception and Antagonism of the Histamine H3 Receptor by Ciproxifan Inhibit Light-Induced Sleep in Mice.

PLoS One 2015 17;10(6):e0128175. Epub 2015 Jun 17.

Department of Biology, Stanford University, Stanford, California, United States of America.

Light has direct effects on sleep and wakefulness causing arousal in diurnal animals and sleep in nocturnal animals. In the present study, we assessed the modulation of light-induced sleep by melanopsin and the histaminergic system by exposing mice to millisecond light flashes and continuous light respectively. First, we show that the induction of sleep by millisecond light flashes is dose dependent as a function of light flash number. We found that exposure to 60 flashes of light occurring once every 60 seconds for 1-h (120-ms of total light over an hour) induced a similar amount of sleep as a continuous bright light pulse. Secondly, the induction of sleep by millisecond light flashes was attenuated in the absence of melanopsin when animals were presented with flashes occurring every 60 seconds over a 3-h period beginning at ZT13. Lastly, the acute administration of a histamine H3 autoreceptor antagonist, ciproxifan, blocked the induction of sleep by a 1-h continuous light pulse during the dark period. Ciproxifan caused a decrease in NREMS delta power and an increase in theta activity during both sleep and wake periods respectively. The data suggest that some form of temporal integration occurs in response to millisecond light flashes, and that this process requires melanopsin photoreception. Furthermore, the pharmacological data suggest that the increase of histaminergic neurotransmission is sufficient to attenuate the light-induced sleep response during the dark period.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0128175PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4471207PMC
March 2016

Nest building is impaired in the Ts65Dn mouse model of Down syndrome and rescued by blocking 5HT2a receptors.

Neurobiol Learn Mem 2014 Dec 29;116:162-71. Epub 2014 Oct 29.

Department of Biology, Stanford University, Stanford, CA 94305, USA. Electronic address:

Down syndrome (DS) has an incidence of about 1/700 births, and is therefore the most common cause of cognitive and behavioral impairments in children. Recent studies on mouse models of DS indicate that a number of pharmacotherapies could be beneficial for restoring cognitive abilities in individuals with DS. Attention deficits that are present in DS account in part for learning and memory deficiencies yet have been scarcely studied in corresponding models. Investigations of this relevant group of behaviors is more difficult in mouse models because of the difficulty in homologizing mouse and human behaviors and because standard laboratory environments do not always elicit behaviors of interest. Here we characterize nest building as a goal-directed behavior that is seriously impaired in young Ts65Dn mice, a genetic model of DS. We believe this impairment may reflect in part attention deficits, and we investigate the physiological, genetic, and pharmacological factors influencing its expression. Nesting behavior in young Ts65Dn mice was severely impaired when the animals were placed in a novel environment. But this context-dependent impairment was transient and reversible. The genetic determinants of this deficiency are restricted to a ∼100 gene segment on the murine chromosome 16. Nest building behavior is a highly integrated phenotypic trait that relies in part on limbic circuitry and on the frontal cortex in relation to cognitive and attention processes. We show that both serotonin content and 5HT2a receptors are increased in the frontal cortex of Ts65Dn mice and that pharmacological blockage of 5HT2a receptors in Ts65Dn mice rescues their context dependent nest building impairment. We propose that the nest-building trait could represent a marker of attention related deficits in DS models and could be of value in designing pharmacotherapies for this specific aspect of DS. 5HT2a modulation may improve goal-directed behavior in DS.
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http://dx.doi.org/10.1016/j.nlm.2014.10.002DOI Listing
December 2014

Adaptive and pathological inhibition of neuroplasticity associated with circadian rhythms and sleep.

Behav Neurosci 2014 Jun;128(3):273-82

Biology Department.

The circadian system organizes sleep and wake through imposing a daily cycle of sleep propensity on the organism. Sleep has been shown to play an important role in learning and memory. Apart from the daily cycle of sleep propensity, however, direct effects of the circadian system on learning and memory also have been well documented. Many mechanistic components of the memory consolidation process ranging from the molecular to the systems level have been identified and studied. The question that remains is how do these various processes and components work together to produce cycles of increased and decreased learning abilities, and why should there be times of day when neural plasticity appears to be restricted? Insights into this complex problem can be gained through investigations of the learning disabilities caused by circadian disruption in Siberian hamsters and by aneuploidy in Down's syndrome mice. A simple working hypothesis that has been explored in this work is that the observed learning disabilities are due to an altered excitation/inhibition balance in the CNS. Excessive inhibition is the suspected cause of deficits in memory consolidation. In this article we present the evidence that excessive inhibition in these cases of learning disability involves GABAergic neurotransmission, that treatment with GABA receptor inhibitors can reverse the learning disability, and that the efficacy of the treatment is time sensitive coincident with the major daily sleep phase, and that it depends on sleep. The evidence we present leads us to hypothesize that a function of the circadian system is to reduce neuroplasticity during the daily sleep phase when processes of memory consolidation are taking place.
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http://dx.doi.org/10.1037/a0036689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4060045PMC
June 2014

Orexin A and orexin receptor 1 axonal traffic in dorsal roots at the CNS/PNS interface.

Front Neurosci 2014 11;8:20. Epub 2014 Feb 11.

Department of Psychiatry and Behavioral Sciences, Center for Sleep Sciences, Beckman Center, Stanford University Stanford, CA, USA ; INSERM 1024, Ecole Normale Supérieure Paris, France.

Hypothalamic orexin/hypocretin neurons send long axonal projections through the dorsal spinal cord in lamina I-II of the dorsal horn (DH) at the interface with the peripheral nervous system (PNS). We show that in the DH OXA fibers colocalize with substance P (SP) positive afferents of dorsal root ganglia (DRG) neurons known to mediate sensory processing. Further, OR1 is expressed in p75(NTR) and SP positive DRG neurons, suggesting a potential signaling pathway between orexin and DRG neurons. Interestingly, DRG sensory neurons have a distinctive bifurcating axon where one branch innervates the periphery and the other one the spinal cord (pseudo-unipolar neurons), allowing for potential functional coupling of distinct targets. We observe that OR1 is transported selectively from DRG toward the spinal cord, while OXA is accumulated retrogradely toward the DRG. We hence report a rare situation of asymmetrical neuropeptide receptor distribution between axons projected by a single neuron. These molecular and cellular data are consistent with the role of OXA/OR1 in sensory processing, including DRG neuronal modulation, and support the potential existence of an OX/HCRT circuit between CNS and PNS.
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http://dx.doi.org/10.3389/fnins.2014.00020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3920189PMC
February 2014

The acute effects of light on murine sleep during the dark phase: importance of melanopsin for maintenance of light-induced sleep.

Eur J Neurosci 2013 Jun 20;37(11):1727-36. Epub 2013 Mar 20.

Department of Biology, Stanford University, Stanford, CA 94305, USA.

Light exerts a direct effect on sleep and wakefulness in nocturnal and diurnal animals, with a light pulse during the dark phase suppressing locomotor activity and promoting sleep in the former. In the present study, we investigated this direct effect of light on various sleep parameters by exposing mice to a broad range of illuminances (0.2-200 μW/cm(2) ; equivalent to 1-1000 lux) for 1 h during the dark phase (zeitgeber time 13-14). Fitting the data with a three-parameter log model indicated that ~0.1 μW/cm(2) can generate half the sleep response observed at 200 μW/cm(2). We observed decreases in total sleep time during the 1 h following the end of the light pulse. Light reduced the latency to sleep from ~30 min in darkness (baseline) to ~10 min at the highest intensity, although this effect was invariant across the light intensities used. We then assessed the role of melanopsin during the rapid transition from wakefulness to sleep at the onset of a light pulse and the maintenance of sleep with a 6-h 20 μW/cm(2) light pulse. Even though the melanopsin knockout mice had robust induction of sleep (~35 min) during the first hour of the pulse, it was not maintained. Total sleep decreased by almost 65% by the third hour in comparison with the first hour of the pulse in mice lacking melanopsin, whereas only an 8% decrease was observed in wild-type mice. Collectively, our findings highlight the selective effects of light on murine sleep, and suggest that melanopsin-based photoreception is primarily involved in sustaining light-induced sleep.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5079684PMC
http://dx.doi.org/10.1111/ejn.12189DOI Listing
June 2013

FoxO6 regulates memory consolidation and synaptic function.

Genes Dev 2012 Dec 7;26(24):2780-801. Epub 2012 Dec 7.

Department of Genetics, Stanford University, Stanford, California 94305, USA.

The FoxO family of transcription factors is known to slow aging downstream from the insulin/IGF (insulin-like growth factor) signaling pathway. The most recently discovered FoxO isoform in mammals, FoxO6, is highly enriched in the adult hippocampus. However, the importance of FoxO factors in cognition is largely unknown. Here we generated mice lacking FoxO6 and found that these mice display normal learning but impaired memory consolidation in contextual fear conditioning and novel object recognition. Using stereotactic injection of viruses into the hippocampus of adult wild-type mice, we found that FoxO6 activity in the adult hippocampus is required for memory consolidation. Genome-wide approaches revealed that FoxO6 regulates a program of genes involved in synaptic function upon learning in the hippocampus. Consistently, FoxO6 deficiency results in decreased dendritic spine density in hippocampal neurons in vitro and in vivo. Thus, FoxO6 may promote memory consolidation by regulating a program coordinating neuronal connectivity in the hippocampus, which could have important implications for physiological and pathological age-dependent decline in memory.
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http://dx.doi.org/10.1101/gad.208926.112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3533081PMC
December 2012

Pumilio-2 function in the mouse nervous system.

PLoS One 2011 7;6(10):e25932. Epub 2011 Oct 7.

Institute for Stem Cell Biology and Regenerative Medicine, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, California, United States of America.

Coordinated mRNA translation at the synapse is increasingly recognized as a critical mechanism for neuronal regulation. Pumilio, a translational regulator, is known to be involved in neuronal homeostasis and memory formation in Drosophila. Most recently, the mammalian Pumilio homolog Pumilio-2 (Pum2) has been found to play a role in the mammalian nervous system, in particular in regulating morphology, arborization and excitability of neuronal dendrites, in vitro. However, the role of Pum2 in vivo remains unclear. Here, we report our investigation of the functional and molecular consequences of Pum2 disruption in vivo using an array of neurophysiology, behavioral and gene expression profiling techniques. We used Pum2-deficient mice to monitor in vivo brain activity using EEG and to study behavior traits, including memory, locomotor activity and nesting capacities. Because of the suspected role of Pum2 in neuronal excitability, we also examined the susceptibility to seizure induction. Finally, we used a quantitative gene expression profiling assay to identify key molecular partners of Pum2. We found that Pum2-deficient mice have abnormal behavioral strategies in spatial and object memory test. Additionally, Pum2 deficiency is associated with increased locomotor activity and decreased body weight. We also observed environmentally-induced impairment in nesting behavior. Most importantly, Pum2-deficient mice showed spontaneous EEG abnormalities and had lower seizure thresholds using a convulsing dosage of pentylenetetrazole. Finally, some genes, including neuronal ion channels, were differentially expressed in the hippocampus of Pum2-deficient mice. These findings demonstrate that Pum2 serves key functions in the adult mammalian central nervous system encompassing neuronal excitability and behavioral response to environmental challenges.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0025932PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3189250PMC
February 2012

Synaptic plasticity in sleep: learning, homeostasis and disease.

Trends Neurosci 2011 Sep 15;34(9):452-63. Epub 2011 Aug 15.

Department of Psychiatry and Behavioral Sciences, Center for Sleep Sciences, Beckman Center, Stanford University, Palo Alto, CA 94305, USA.

Sleep is a fundamental and evolutionarily conserved aspect of animal life. Recent studies have shed light on the role of sleep in synaptic plasticity. Demonstrations of memory replay and synapse homeostasis suggest that one essential role of sleep is in the consolidation and optimization of synaptic circuits to retain salient memory traces despite the noise of daily experience. Here, we review this recent evidence and suggest that sleep creates a heightened state of plasticity, which may be essential for this optimization. Furthermore, we discuss how sleep deficits seen in diseases such as Alzheimer's disease and autism spectrum disorders might not just reflect underlying circuit malfunction, but could also play a direct role in the progression of those disorders.
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http://dx.doi.org/10.1016/j.tins.2011.07.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3385863PMC
September 2011

Optogenetic disruption of sleep continuity impairs memory consolidation.

Proc Natl Acad Sci U S A 2011 Aug 25;108(32):13305-10. Epub 2011 Jul 25.

Departments of Psychiatry and Behavioral Science and Biology, Stanford University, Stanford, CA 94305-5020, USA.

Memory consolidation has been proposed as a function of sleep. However, sleep is a complex phenomenon characterized by several features including duration, intensity, and continuity. Sleep continuity is disrupted in different neurological and psychiatric conditions, many of which are accompanied by memory deficits. This finding has raised the question of whether the continuity of sleep is important for memory consolidation. However, current techniques used in sleep research cannot manipulate a single sleep feature while maintaining the others constant. Here, we introduce the use of optogenetics to investigate the role of sleep continuity in memory consolidation. We optogenetically targeted hypocretin/orexin neurons, which play a key role in arousal processes. We used optogenetics to activate these neurons at different intervals in behaving mice and were able to fragment sleep without affecting its overall amount or intensity. Fragmenting sleep after the learning phase of the novel object recognition (NOR) task significantly decreased the performance of mice on the subsequent day, but memory was unaffected if the average duration of sleep episodes was maintained at 62-73% of normal. These findings demonstrate the use of optogenetic activation of arousal-related nuclei as a way to systematically manipulate a specific feature of sleep. We conclude that regardless of the total amount of sleep or sleep intensity, a minimal unit of uninterrupted sleep is crucial for memory consolidation.
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http://dx.doi.org/10.1073/pnas.1015633108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3156195PMC
August 2011

Melanopsin as a sleep modulator: circadian gating of the direct effects of light on sleep and altered sleep homeostasis in Opn4(-/-) mice.

PLoS Biol 2009 Jun 9;7(6):e1000125. Epub 2009 Jun 9.

Department of Biology, Stanford University, Stanford, CA, USA.

Light influences sleep and alertness either indirectly through a well-characterized circadian pathway or directly through yet poorly understood mechanisms. Melanopsin (Opn4) is a retinal photopigment crucial for conveying nonvisual light information to the brain. Through extensive characterization of sleep and the electrocorticogram (ECoG) in melanopsin-deficient (Opn4(-/-)) mice under various light-dark (LD) schedules, we assessed the role of melanopsin in mediating the effects of light on sleep and ECoG activity. In control mice, a light pulse given during the habitual dark period readily induced sleep, whereas a dark pulse given during the habitual light period induced waking with pronounced theta (7-10 Hz) and gamma (40-70 Hz) activity, the ECoG correlates of alertness. In contrast, light failed to induce sleep in Opn4(-/-) mice, and the dark-pulse-induced increase in theta and gamma activity was delayed. A 24-h recording under a LD 1-hratio1-h schedule revealed that the failure to respond to light in Opn4(-/-) mice was restricted to the subjective dark period. Light induced c-Fos immunoreactivity in the suprachiasmatic nuclei (SCN) and in sleep-active ventrolateral preoptic (VLPO) neurons was importantly reduced in Opn4(-/-) mice, implicating both sleep-regulatory structures in the melanopsin-mediated effects of light. In addition to these acute light effects, Opn4(-/-) mice slept 1 h less during the 12-h light period of a LD 12ratio12 schedule owing to a lengthening of waking bouts. Despite this reduction in sleep time, ECoG delta power, a marker of sleep need, was decreased in Opn4(-/-) mice for most of the (subjective) dark period. Delta power reached after a 6-h sleep deprivation was similarly reduced in Opn4(-/-) mice. In mice, melanopsin's contribution to the direct effects of light on sleep is limited to the dark or active period, suggesting that at this circadian phase, melanopsin compensates for circadian variations in the photo sensitivity of other light-encoding pathways such as rod and cones. Our study, furthermore, demonstrates that lack of melanopsin alters sleep homeostasis. These findings call for a reevaluation of the role of light on mammalian physiology and behavior.
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http://dx.doi.org/10.1371/journal.pbio.1000125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2688840PMC
June 2009

Sleep and EEG features in genetic models of Down syndrome.

Neurobiol Dis 2008 Apr 21;30(1):1-7. Epub 2007 Jul 21.

Center for Narcolepsy, Department of Psychiatry and Behavioral Sciences, Stanford, CA 94305, USA.

Down syndrome is characterized by a host of behavioral abnormalities including sleep disturbances. Sleep and EEG was studied at the age of 3 months in two mouse models of the condition, Ts65Dn and Ts1Cje, carrying one extra copy of partially overlapping segments of the mmu chromosome 16 (equivalent to the human chromosome 21). We found that the Ts65Dn mice showed increased waking amounts at the expense of non-REM sleep, increased theta power during sleep and a delayed sleep rebound after sleep deprivation. In contrast, Ts1Cje had limited sleep and EEG abnormalities, showing only a delayed sleep rebound after sleep deprivation and no difference in theta power. We previously found that mice over-expressing the human APPwt transgene, a gene triplicated in Ts65Dn but not Ts1Cje, also show increased wake and theta power during sleep. These results demonstrate abnormalities in sleep and EEG in Ts65Dn mice and underscore a possible correlation between App overexpression and hippocampal theta oscillations.
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http://dx.doi.org/10.1016/j.nbd.2007.07.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4689324PMC
April 2008

Regional age-related changes in neuronal nitric oxide synthase (nNOS), messenger RNA levels and activity in SAMP8 brain.

BMC Neurosci 2006 Dec 21;7:81. Epub 2006 Dec 21.

EA 3734, Faculty of Medecine, Claude Bernard University, 69373 Lyon, France.

Background: Nitric oxide (NO) is a multifunctional molecule synthesized by three isozymes of the NO synthase (NOSs) acting as a messenger/modulator and/or a potential neurotoxin. In rodents, the role of NOSs in sleep processes and throughout aging is now well established. For example, sleep parameters are highly deteriorated in senescence accelerated-prone 8 (SAMP8) mice, a useful animal model to study aging or age-associated disorders, while the inducible form of NOS (iNOS) is down-regulated within the cortex and the sleep-structures of the brainstem. Evidence is now increasing for a role of iNOS and resulting oxidative stress but not for the constitutive expressed isozyme (nNOS). To better understand the role of nNOS in the behavioural impairments observed in SAMP8 versus SAMR1 (control) animals, we evaluated age-related variations occurring in the nNOS expression and activity and nitrites/nitrates (NOx-) levels, in three brain areas (n = 7 animals in each group). Calibrated reverse transcriptase (RT) and real-time polymerase chain reaction (PCR) and biochemical procedures were used.

Results: We found that the levels of nNOS mRNA decreased in the cortex and the hippocampus of 8- vs 2-month-old animals followed by an increase in 12-vs 8-month-old animals in both strains. In the brainstem, levels of nNOS mRNA decreased in an age-dependent manner in SAMP8, but not in SAMR1. Regional age-related changes were also observed in nNOS activity. Moreover, nNOS activity in hippocampus was found lower in 8-month-old SAMP8 than in SAMR1, while in the cortex and the brainstem, nNOS activities increased at 8 months and afterward decreased with age in SAMP8 and SAMR1. NOx- levels showed profiles similar to nNOS activities in the cortex and the brainstem but were undetectable in the hippocampus of SAMP8 and SAMR1. Finally, NOx- levels were higher in the cortex of 8 month-old SAMP8 than in age-matched SAMR1.

Conclusion: Concomitant variations occurring in NO levels derived from nNOS and iNOS at an early age constitute a major factor of risk for sleep and/or memory impairments in SAMP8.
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http://dx.doi.org/10.1186/1471-2202-7-81DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1766358PMC
December 2006

REM sleep control during aging in SAM mice: a role for inducible nitric oxide synthase.

Neurobiol Aging 2005 Nov-Dec;26(10):1375-84. Epub 2004 Dec 22.

Institut National de la Santé et de la Recherche Médicale EA3734, Department of Experimental Medicine, Faculty of Medecine, Claude Bernard University, Lyon Cedex 08 69373, France.

Evidence that nitric oxide (NO) is involved in the regulation of rapid-eye-movement sleep (REMS) is supported by recent studies. During aging, NO generation encounters marked changes mainly related to the activation of the inducible NO-synthase (iNOS). To investigate links existing between iNOS and REMS impairments related to aging, we examine the age-related variations occurring in: mRNA and activity of iNOS in brainstem and frontal cortex; sleep parameters under baseline and after treatment by a selective iNOS inhibitor (AMT) in Senescence Accelerated Mice (SAM). SAMR1 (control) mice are a model of aging while SAMP8 are adequate to study neurodegenerative processes. RT-PCR analysis does not reveal significant variation in iNOS mRNA expression in both strains. However, significant age-related increases in iNOS activity occur in SAMR1 but such variation is not observed in SAMP8. In baseline conditions, aging induces a slight increase in slow-wave sleep (SWS) amounts in both groups and deteriorates greatly REMS architecture in SAMP8 compared to SAMR1. AMT reduces REMS amounts for 4-6h after treatment in a dose and age-dependent manner in SAMR1. Almost no changes occur in SAMP8. Data reported suggest that NO derived from iNOS contributes to trigger and maintain REMS during aging.
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http://dx.doi.org/10.1016/j.neurobiolaging.2004.11.002DOI Listing
January 2006

Sleep disturbances in Ube3a maternal-deficient mice modeling Angelman syndrome.

Neurobiol Dis 2005 Nov;20(2):471-8

EA 3734, Claude Bernard University, 8 av. Rockefeller, 69373 Lyon Cedex 08, France.

Background: Angelman syndrome (AS) is a severe neurodevelopmental disorder with electroencephalographic (EEG) abnormalities and sleep disturbances. It results from lack of the functional maternal allele of UBE3A, which encodes a ubiquitin-protein ligase. Different mechanisms of UBE3A inactivation correlate with clinical phenotypes of varying severity; the majority of cases of AS are due to a de novo maternal deletion of the 15q11-q13 region.

Methods: Ube3a maternal-deficient mice (Ube3a m-/p+) were generated in a C57Bl/6J background. This study compares cortical EEG and architecture of the sleep-waking cycle in adult Ube3a m-/p+ mice compared with those of age-matched WT (m+/p+) mice, under baseline conditions or after 4-h sleep deprivation (SD).

Results: Ube3a m-/p+ mice exhibited: reduced slow-wave sleep (SWS) amount with increase waking (W) at the dark/light transitions; increased SWS and W episode numbers; and deterioration of paradoxical sleep (PS) over 24 h [amount: -44%; episode duration: -46%; episode number: -40%; theta peak frequency (TPF) acceleration: 7.6 Hz vs. 7.0 Hz in WT mice]. Characteristic paroxysmal EEG discharges are observed during W and SWS associated with synchronous muscle bursting activity during hypoactive W. During the recovery period following SD, Ube3a m-/p+ mice exhibited no rebound either in slow-wave activity (+89% in WT) or in delta-power spectra but a slight rebound in PS amount (+20%).

Conclusions: These data validate the mouse model produced by null mutation of the maternal Ube3a gene and provide useful results to investigate and better understand the molecular basis of sleep disturbances in AS patients.
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http://dx.doi.org/10.1016/j.nbd.2005.04.003DOI Listing
November 2005

Nitric oxide and sleep.

Sleep Med Rev 2005 Apr;9(2):101-13

Claude Bernard University Lyon1, INSERM U 480, EA 3734 and IFR 19, 8 avenue Rockefeller, F-69373 Lyon Cedex 08, France.

Nitric oxide (NO) is a biological messenger synthesized by three main isoforms of NO synthase (NOS): neuronal (nNOS, constitutive calcium dependent), endothelial (eNOS, constitutive, calcium dependent) and inducible (iNOS, calcium independent). NOS is distributed in the brain either in circumscribed neuronal sets or in sparse interneurons. Within the laterodorsal tegmentum (LDT), pedunculopontine tegmentum and dorsal raphe nucleus, NOS-containing neurons overlap neurons grouped according to their contribution to sleep mechanisms. The main target for NO is the soluble guanylate cyclase that triggers an overproduction of cyclic guanosine monophosphate. NO in neurons of the pontine tegmentum facilitates sleep (particularly rapid-eye-movement sleep), and NO contained within the LDT intervenes in modulating the discharge of the neurons through an auto-inhibitory process involving the co-synthesized neurotransmitters. Moreover, NO synthesized within cholinergic neurons of the basal forebrain, while under control of the LDT, may modulate the spectral components of the EEG instead of the amounts of different sleep states. Finally, impairment of NO production (e.g. neurodegeneration, iNOS induction) has identifiable effects, including ageing, neuropathologies and parasitaemia.
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http://dx.doi.org/10.1016/j.smrv.2004.07.004DOI Listing
April 2005

Sleep wake profile and EEG spectral power in young or old senescence accelerated mice.

Neurobiol Aging 2005 Feb;26(2):265-73

INSERM Unit 480, Claude Bernard University, 8 Avenue Rockefeller, 69373 Lyon Cedex 08, France.

Changes occurring with age in cortical EEG and sleep-wake states architecture were examined in senescence accelerated prone (SAMP8) or senescence resistant (SAMR1) mice (age: 2 and 12 months) under baseline conditions or after a 4 h sleep deprivation (SD). In baseline conditions, an increase in slow wave sleep (SWS) amount (21-24%) occurs at the expense of the wakefulness (W) in old SAMP8 and SAMR1 mice versus young animals. In these conditions, SWS latency is reduced (67-72%). Moreover, in SAMP8 and SAMR1 mice, aging deteriorates paradoxical sleep (PS) architecture with more pronounced changes in SAMP8 (amount: -63%; episode duration: -44%; latency: +286%; circadian component loss; and EEG theta (theta) peak frequency (TPF): -1 Hz). During the 4 h recovery subsequent to a 4 h sleep deprivation, old SAMP8 mice exhibit an enhanced sensitivity resulting in SWS (+62%) and PS (+120%) rebounds, a characteristic of this inbred strain. Results obtained are discussed in line with the age-related learning and memory impairments existing in SAMP8 animals. In particular, the reduced cognitive performances described in old SAMP8 might be linked to the TPF deterioration during PS.
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http://dx.doi.org/10.1016/j.neurobiolaging.2004.03.004DOI Listing
February 2005

Sleep-wake architecture in mouse models for Down syndrome.

Neurobiol Dis 2004 Jul;16(2):291-9

Unite INSERM Unit 480, Claude Bernard University, 69373 Lyon Cedex 08, France.

Sleep-wake homeostasis is crucial for behavioral performances and memory both in the general population and in patients with learning disability, among whom were Down syndrome (DS) patients. We investigated, in mouse models of DS, cortical EEG and sleep-wake architecture under baseline conditions and after a 4-h sleep deprivation (SD). Young hemizygous mice (hSODwt/+) transgenic for the human CuZn superoxide dismutase (hSOD1) or for the human amyloid precursor protein (HuAPP(695); hAPPwt/+) were obtained on the same FVB/N inbred background. Baseline records for slow wave sleep (SWS) and wake (W) parameters were unchanged, whereas paradoxical sleep (PS) episode numbers were decreased and PS latency increased after lights off in hSODwt/+ mice versus controls. hSODwt/+ mice did not experience SWS or PS rebounds after SD but EEG activity in the delta-SWS activity (SWA) was enhanced. hAPPwt/+ mice exhibited no change in PS but an increase in W and a decrease in SWS before light transition as well as an increase in theta-power in PS and W. After SD, hAPPwt/+ mice exhibited SWS and PS rebounds as well as enhancement of SWA. We investigated also the nitrite/nitrate levels in all mice and found an increase in the brainstem of hSODwt/+ mice only versus control ones. These preliminary data provide useful results to investigate other genetically manipulated mice and to better understand the biochemical basis of sleep disorders in DS patients.
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http://dx.doi.org/10.1016/j.nbd.2004.03.009DOI Listing
July 2004