Sleep Cycle Oscillation: Reciprocal Discharge by Two Brainstem Neuronal Groups

Hobson, J. Allan; McCarley, Robert W.; Wyzinski, P.

doi:10.1126/science.1094539

Cited by 1,119 publications

(528 citation statements)

References 12 publications

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“…Complex attractors represent imperfect oscillators within bounded orbits, modeling periodic functions common in nature. Oscillatory cycling (Hobson et al, 1975) and chaotic attractors (McCarley and Massaquoi, 1986) modeled REM on the basis of REM-on and REM-off neuronal activities. The argument regarding the existence of ultradian oscillators is far from closed, as it is becoming increasingly difficult to refute the likelihood of a genetic regulation of sleep physiology and its ultradian markers.…”

Section: Discussionmentioning

confidence: 99%

Treatment Enhances Ultradian Rhythms of CSF Monoamine Metabolites in Patients with Major Depressive Episodes

Salomon

Kennedy

Johnson

et al. 2005

Neuropsychopharmacol

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Unipolar and bipolar depressions show abnormal behavioral manifestations of ultradian (less than 24 h) rhythms, but abnormal rhythms of the central neurotransmitters thought to be important for depression pathophysiology (eg dopamine (DA) and serotonin (5-HT)) have not been shown in this time frame. Since antidepressant treatments normalize disrupted rhythms in depression (eg rapid-eyemovement sleep and hormonal rhythms), we hypothesized that depression-related changes in ultradian oscillations of DA and 5-HT might be revealed during antidepressant treatment. Cerebrospinal fluid (CSF) samples collected q10 min for 24 h in 13 patients experiencing major depressive episodes (MDE) before and after treatment for 5 weeks with sertraline or bupropion were assayed for levels of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA), and their ratio was calculated. Data were analyzed in the frequency domain using Fourier transforms and multivariate permutation testing. Antidepressant treatments were associated with decreased variance for 5-HIAA, increased variance for HVA, and markedly increased variance for the HVA : 5-HIAA ratio (po0.05, po0.02, and po0.003, respectively). With treatment, the correlations between 5-HIAA and HVA weakened (p ¼ 0.06). Power spectral density (PSDFthe Fourier magnitude squared) of the 5-HIAA signals at periods of 1.75 and 3.7 h (both po0.05) decreased, while circadian cycling of HVA levels (po0.05) and of the ratio (po0.005) increased after treatment. The PSD of the full-length HVA : 5-HIAA ratio series after treatment increased in rapid variability (20-103 min periods, po0.05). Spectrographic windowing demonstrated a focal span of enhanced HVA : 5-HIAA ratio variability following antidepressant treatment, in an approximately 84-min period through the evening (po0.05). Periodic neurotransmitter relationships in depressed patients were altered by treatment in this analysis of a small data set. This may represent a baseline abnormality in the regulation of periodic functions involved in the depression pathophysiology, but it could also be due to an unrelated antidepressant effect. Further studies including comparisons with healthy subject data are in progress.

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Section: Discussionmentioning

confidence: 99%

Treatment Enhances Ultradian Rhythms of CSF Monoamine Metabolites in Patients with Major Depressive Episodes

Salomon

Kennedy

Johnson

et al. 2005

Neuropsychopharmacol

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“…23) The discharge activity of these neurons is highest during waking, decreases during slow-wave sleep, and is virtually absent during REM sleep. [4][5][6] In the absence of REM sleep, these neurons fire continuously, resulting in reduced receptor sensitivity 24,25) and changes associated with NA synthesis and metabolism. 26,27) Actually, the turnover and metabolism of NA are elevated both during and after REMSD.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, there may be a positive association between this animal model and a hyperfunctional status of noradrenergic systems since the firing of noradrenergic neurons in locus ceruleus (LC) continuous during rapid eye movement (REM) sleep deprivation. [4][5][6] ADHD is a childhood psychiatric disorder characterized by the presence of symptoms in three domains: inattention, impulsivity, and motor overactivity. 7) It has been suggested that these symptoms may be due to a combination of alerting deficits and executive-control deficits involving the prefrontal cortex.…”

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confidence: 99%

Effects of Atomoxetine on Levels of Monoamines and Related Substances in Discrete Brain Regions in Mice Intermittently Deprived of Rapid Eye Movement Sleep

Niijima

Saito

Murai

et al. 2010

Biological & Pharmaceutical Bulletin

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Sleep deprivation represents a common type of stress that can, when extreme, lead to psychological and physiological damage, and even death, in experimental animals. 1) After a period of intermittent rapid eye movement sleep deprivation (REMSD) (72-96 h), rats stay awake for approximately 30 min, and during this period display hyperactivity, irritability, aggressiveness, and hypersexuality. 2) Recently, we showed in mice that 5 days' intermittent REMSD (20 h/d) results in explosive jumping behavior. This behavior was antagonized dose-dependently and significantly by treatment with atomoxetine (0.41-0.55 mg/kg, subcutaneously (s.c.)), which is used clinically to treat the symptoms of attention deficit/hyperactivity disorder (ADHD), 3) raising the possibility such jumping behavior may serve as a useful animal model of ADHD. Moreover, there may be a positive association between this animal model and a hyperfunctional status of noradrenergic systems since the firing of noradrenergic neurons in locus ceruleus (LC) continuous during rapid eye movement (REM) sleep deprivation. [4][5][6] ADHD is a childhood psychiatric disorder characterized by the presence of symptoms in three domains: inattention, impulsivity, and motor overactivity. 7) It has been suggested that these symptoms may be due to a combination of alerting deficits and executive-control deficits involving the prefrontal cortex. 8,9) Although existing studies contain several inconsistencies, on balance the evidence supports dysfunctions of the fronto-striatal neuronal circuits regulated by dopaminergic and noradrenergic afferents, with resultant executive deficits in cognitive functioning. [7][8][9][10] The stimulants amphetamine and methylphenidate, which are indirect agonist that increase extracellular monoamine concentration by inhibiting reuptake and/or promoting release, are the primary treatment for ADHD. 11) The efficacy of stimulants suggests that dopaminergic and/or noradrenergic dysregulation contribute to the expression of ADHD, while diversity in psychostimulant response suggests that the ADHD is not attributable to any single pathophysiologic mechanism. In the absence of specific therapeutic targets, the treatment strategy progresses from stimulant to non-stimulant drugs. 12) Atomoxetine is a non-stimulant drug and a selective inhibitor of the presynaptic noradrenaline (NA)-reuptake transporter (NAT). Indeed, it has an approximately 300-fold selectivity for NAT over the dopamine (DA)-uptake transporter (DAT), a finding that has increased interest in the role of NAT and noradrenergic systems in ADHD. 13) In the frontal cortex, NAT density is higher than DAT density, [14][15][16] and NAT blockade by atomoxetine is thought to block sequestration of DA into NA neurons. 13) Moreover, NAT is poorly expressed in the striatum, in contrast to its robust expression within the frontal cortex. 13) The above findings suggest that the therapeutic effects of drugs that block NAT are mediated by increasing both NA and DA in noradrenergic terminal areas such as ...

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“…In doing so I will test the current understanding of the role the SubC plays in maintaining motor atonia. Furthermore, I will provide the quantitative muscle tone analysis lacking in existing SubC studies [12]. A knockout mouse which does not express the hypocretin ligand was developed, and it displayed sleep dysregulation which is similar to both human and canine narcolepsy.…”

Section: Section 2 -Aimsmentioning

confidence: 99%

Pharmacogenetic inhibition of the subcoeruleus region influences rem sleep and cataplexy in narcoleptic mice

2013

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Introduction: Cataplexy -the sudden involuntary loss of skeletal muscle tone -is a defining feature of narcolepsy. The current study aimed to determine if cataplexy is influenced by direct manipulation of REM sleep circuitry. We did this by pharmacogenetically inhibiting the REM sleep centre, subcoeruleus (Sub-C). Methods:Inhibitory DREADD (hM4D-Gi) was bilaterally targeted to the Sub-C in hypocretin knockout mice (n=7). Intraperitoneal administration of clozapine-n-oxide was used to inhibit Sub-C cells expressing hM4D-Gi. Electrophysiological and behavioural criteria were used to characterize cataplexy and REM sleep.Results: Sub-C inhibition increased REM sleep and cataplexy amounts (p<0.05). Sub-C inhibition increased time spent in cataplexy amounts by increasing the number of cataplexy attacks (p<0.05). This intervention triggered increases in basal muscle tone during REM sleep, but had negligible effects on muscle tone during cataplexy (p>0.05).ii Conclusion: Pharmacogenetic manipulation of the Sub-C suggest that REM sleep and cataplexy are mediate by similar neural mechanism.iii

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Sleep Cycle Oscillation: Reciprocal Discharge by Two Brainstem Neuronal Groups

Cited by 1,119 publications

References 12 publications

Treatment Enhances Ultradian Rhythms of CSF Monoamine Metabolites in Patients with Major Depressive Episodes

Treatment Enhances Ultradian Rhythms of CSF Monoamine Metabolites in Patients with Major Depressive Episodes

Effects of Atomoxetine on Levels of Monoamines and Related Substances in Discrete Brain Regions in Mice Intermittently Deprived of Rapid Eye Movement Sleep

Pharmacogenetic inhibition of the subcoeruleus region influences rem sleep and cataplexy in narcoleptic mice

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