Circadian and histaminergic regulation of the sleep-wakefulness cycle

Research output: ThesisDoctoral ThesisCollection of Articles

Abstract

The histaminergic neurons of the hypothalamus in conjunction with hypocretinergic cells, monoaminergic nuclei of the brainstem and basal forebrain centers, constitute the ascending arousal system that plays a pivotal role in maintenance of wakefulness state. It has predominantly inhibitory reciprocal connections to their sleep-active counterparts, which enables an efficient transition between wakefulness and sleep. In combination with the circadian clock and homeostatic regulation of sleep its forms a network that regulate the sleep-wakefulness cycle. Because of the complex organization, it becomes difficult to estimate the significance of the crosstalk between the individual components of this regulatory network. Therefore, we focused on examination of interactions between the histaminergic system, the circadian and homeostatic components. We used electroencephalography in combination with behavioral analysis to quantify changes in spontaneous locomotion, wakefulness, non-rapid eye movement sleep and rapid eye movement sleep stages in response to an alterations of pacemaker rhythm. The shortening of the light-dark cycle led to re-distribution of these parameters towards aperiodicity, as well as increased sleep propensity, diminished daily rhythms of power of high θ-, and γ-waves, which are characteristic of an active wakefulness state as well as strengthened the phase-amplitude coupling between these frequencies. We used in vivo microdialysis in combination with sleep deprivation to understand the histaminergic regulation of homeostatic sleep propensity. During 6-hours of sleep deprivation, the histamine release was upregulated and comparable to its level during wakefulness, whereas when the sleep deprivation ceased, the release of histamine immediately dropped to the baseline level. To assess the effects of circadian regulation on histaminergic neurons, we estimated the daily changes of activities of the key enzymes involved in the histamine metabolism, histidine decarboxylase and histamine-N-methyltransferase as well as diurnal profile of histamine release. The 24-hour rhythms of production and release of histamine and its metabolite, 1-methylhistamine were detected, whereas activities of the enzymes had no detectable diurnal rhythm. Histamine release was highly positively correlated with changes in the power of the θ-frequency range. In order to understand the possible role of the histaminergic regulation of circadian system functioning we utilized mouse strains that constitutively lack histamine 1 and 3 receptors. The lack of histamine 1 receptor had no effects on the circadian rhythm of spontaneous locomotion, but the knockout of the histamine 3 receptor resulted in a substantial reduction of free-running activity rhythm amplitude. The expressions of the core clock genes, Per1, Per2 and Bmal1, in the suprachiasmatic nuclei of the hypothalamus, the cerebral cortex and the striatum were not affected in these knockout models. Based on the acquired results we concluded that the circadian process may affect homeostatic regulation, thus indicating an interaction of these processes. The circadian regulation of the histaminergic neurons takes place mainly at the level of histamine accumulation and release. In contrast, alterations in histamine-mediated signal transduction caused only minor alterations in examined circadian rhythms. Finally, we could not find evidence of an involvement of the histamine in homeostatic regulation of sleep-wakefulness cycle.
Original languageEnglish
Place of PublicationHelsinki
Publisher
Print ISBNs978-951-51-2135-6
Electronic ISBNs978-951-51-2136-3
Publication statusPublished - 2016
MoE publication typeG5 Doctoral dissertation (article)

Fields of Science

  • 3112 Neurosciences
  • 3111 Biomedicine

Cite this

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title = "Circadian and histaminergic regulation of the sleep-wakefulness cycle",
abstract = "The histaminergic neurons of the hypothalamus in conjunction with hypocretinergic cells, monoaminergic nuclei of the brainstem and basal forebrain centers, constitute the ascending arousal system that plays a pivotal role in maintenance of wakefulness state. It has predominantly inhibitory reciprocal connections to their sleep-active counterparts, which enables an efficient transition between wakefulness and sleep. In combination with the circadian clock and homeostatic regulation of sleep its forms a network that regulate the sleep-wakefulness cycle. Because of the complex organization, it becomes difficult to estimate the significance of the crosstalk between the individual components of this regulatory network. Therefore, we focused on examination of interactions between the histaminergic system, the circadian and homeostatic components. We used electroencephalography in combination with behavioral analysis to quantify changes in spontaneous locomotion, wakefulness, non-rapid eye movement sleep and rapid eye movement sleep stages in response to an alterations of pacemaker rhythm. The shortening of the light-dark cycle led to re-distribution of these parameters towards aperiodicity, as well as increased sleep propensity, diminished daily rhythms of power of high θ-, and γ-waves, which are characteristic of an active wakefulness state as well as strengthened the phase-amplitude coupling between these frequencies. We used in vivo microdialysis in combination with sleep deprivation to understand the histaminergic regulation of homeostatic sleep propensity. During 6-hours of sleep deprivation, the histamine release was upregulated and comparable to its level during wakefulness, whereas when the sleep deprivation ceased, the release of histamine immediately dropped to the baseline level. To assess the effects of circadian regulation on histaminergic neurons, we estimated the daily changes of activities of the key enzymes involved in the histamine metabolism, histidine decarboxylase and histamine-N-methyltransferase as well as diurnal profile of histamine release. The 24-hour rhythms of production and release of histamine and its metabolite, 1-methylhistamine were detected, whereas activities of the enzymes had no detectable diurnal rhythm. Histamine release was highly positively correlated with changes in the power of the θ-frequency range. In order to understand the possible role of the histaminergic regulation of circadian system functioning we utilized mouse strains that constitutively lack histamine 1 and 3 receptors. The lack of histamine 1 receptor had no effects on the circadian rhythm of spontaneous locomotion, but the knockout of the histamine 3 receptor resulted in a substantial reduction of free-running activity rhythm amplitude. The expressions of the core clock genes, Per1, Per2 and Bmal1, in the suprachiasmatic nuclei of the hypothalamus, the cerebral cortex and the striatum were not affected in these knockout models. Based on the acquired results we concluded that the circadian process may affect homeostatic regulation, thus indicating an interaction of these processes. The circadian regulation of the histaminergic neurons takes place mainly at the level of histamine accumulation and release. In contrast, alterations in histamine-mediated signal transduction caused only minor alterations in examined circadian rhythms. Finally, we could not find evidence of an involvement of the histamine in homeostatic regulation of sleep-wakefulness cycle.",
keywords = "Brain, +physiology, Biological Clocks, Cerebral Cortex, +drug effects, Cholinergic Neurons, Circadian Rhythm, Dose-Response Relationship, Drug, Electroencephalography, Electromyography, Histamine, +metabolism, Histamine Agonists, Histamine Antagonists, Histamine Release, Hypothalamus, Prosencephalon, Sleep Deprivation, +physiopathology, Sleep Stages, Time Factors, Wakefulness, 3112 Neurosciences, 3111 Biomedicine",
author = "Stanislav Rozov",
note = "M1 - 69 s. + liitteet Helsingin yliopisto Volume: Proceeding volume:",
year = "2016",
language = "English",
isbn = "978-951-51-2135-6",
series = "Dissertationes Scholae Doctoralis Ad Sanitatem Investigandam Universitatis Helsinkiensis",
publisher = "University of Helsinki",
number = "33/2016",
address = "Finland",

}

Circadian and histaminergic regulation of the sleep-wakefulness cycle. / Rozov, Stanislav.

Helsinki : University of Helsinki, 2016. 69 p.

Research output: ThesisDoctoral ThesisCollection of Articles

TY - THES

T1 - Circadian and histaminergic regulation of the sleep-wakefulness cycle

AU - Rozov, Stanislav

N1 - M1 - 69 s. + liitteet Helsingin yliopisto Volume: Proceeding volume:

PY - 2016

Y1 - 2016

N2 - The histaminergic neurons of the hypothalamus in conjunction with hypocretinergic cells, monoaminergic nuclei of the brainstem and basal forebrain centers, constitute the ascending arousal system that plays a pivotal role in maintenance of wakefulness state. It has predominantly inhibitory reciprocal connections to their sleep-active counterparts, which enables an efficient transition between wakefulness and sleep. In combination with the circadian clock and homeostatic regulation of sleep its forms a network that regulate the sleep-wakefulness cycle. Because of the complex organization, it becomes difficult to estimate the significance of the crosstalk between the individual components of this regulatory network. Therefore, we focused on examination of interactions between the histaminergic system, the circadian and homeostatic components. We used electroencephalography in combination with behavioral analysis to quantify changes in spontaneous locomotion, wakefulness, non-rapid eye movement sleep and rapid eye movement sleep stages in response to an alterations of pacemaker rhythm. The shortening of the light-dark cycle led to re-distribution of these parameters towards aperiodicity, as well as increased sleep propensity, diminished daily rhythms of power of high θ-, and γ-waves, which are characteristic of an active wakefulness state as well as strengthened the phase-amplitude coupling between these frequencies. We used in vivo microdialysis in combination with sleep deprivation to understand the histaminergic regulation of homeostatic sleep propensity. During 6-hours of sleep deprivation, the histamine release was upregulated and comparable to its level during wakefulness, whereas when the sleep deprivation ceased, the release of histamine immediately dropped to the baseline level. To assess the effects of circadian regulation on histaminergic neurons, we estimated the daily changes of activities of the key enzymes involved in the histamine metabolism, histidine decarboxylase and histamine-N-methyltransferase as well as diurnal profile of histamine release. The 24-hour rhythms of production and release of histamine and its metabolite, 1-methylhistamine were detected, whereas activities of the enzymes had no detectable diurnal rhythm. Histamine release was highly positively correlated with changes in the power of the θ-frequency range. In order to understand the possible role of the histaminergic regulation of circadian system functioning we utilized mouse strains that constitutively lack histamine 1 and 3 receptors. The lack of histamine 1 receptor had no effects on the circadian rhythm of spontaneous locomotion, but the knockout of the histamine 3 receptor resulted in a substantial reduction of free-running activity rhythm amplitude. The expressions of the core clock genes, Per1, Per2 and Bmal1, in the suprachiasmatic nuclei of the hypothalamus, the cerebral cortex and the striatum were not affected in these knockout models. Based on the acquired results we concluded that the circadian process may affect homeostatic regulation, thus indicating an interaction of these processes. The circadian regulation of the histaminergic neurons takes place mainly at the level of histamine accumulation and release. In contrast, alterations in histamine-mediated signal transduction caused only minor alterations in examined circadian rhythms. Finally, we could not find evidence of an involvement of the histamine in homeostatic regulation of sleep-wakefulness cycle.

AB - The histaminergic neurons of the hypothalamus in conjunction with hypocretinergic cells, monoaminergic nuclei of the brainstem and basal forebrain centers, constitute the ascending arousal system that plays a pivotal role in maintenance of wakefulness state. It has predominantly inhibitory reciprocal connections to their sleep-active counterparts, which enables an efficient transition between wakefulness and sleep. In combination with the circadian clock and homeostatic regulation of sleep its forms a network that regulate the sleep-wakefulness cycle. Because of the complex organization, it becomes difficult to estimate the significance of the crosstalk between the individual components of this regulatory network. Therefore, we focused on examination of interactions between the histaminergic system, the circadian and homeostatic components. We used electroencephalography in combination with behavioral analysis to quantify changes in spontaneous locomotion, wakefulness, non-rapid eye movement sleep and rapid eye movement sleep stages in response to an alterations of pacemaker rhythm. The shortening of the light-dark cycle led to re-distribution of these parameters towards aperiodicity, as well as increased sleep propensity, diminished daily rhythms of power of high θ-, and γ-waves, which are characteristic of an active wakefulness state as well as strengthened the phase-amplitude coupling between these frequencies. We used in vivo microdialysis in combination with sleep deprivation to understand the histaminergic regulation of homeostatic sleep propensity. During 6-hours of sleep deprivation, the histamine release was upregulated and comparable to its level during wakefulness, whereas when the sleep deprivation ceased, the release of histamine immediately dropped to the baseline level. To assess the effects of circadian regulation on histaminergic neurons, we estimated the daily changes of activities of the key enzymes involved in the histamine metabolism, histidine decarboxylase and histamine-N-methyltransferase as well as diurnal profile of histamine release. The 24-hour rhythms of production and release of histamine and its metabolite, 1-methylhistamine were detected, whereas activities of the enzymes had no detectable diurnal rhythm. Histamine release was highly positively correlated with changes in the power of the θ-frequency range. In order to understand the possible role of the histaminergic regulation of circadian system functioning we utilized mouse strains that constitutively lack histamine 1 and 3 receptors. The lack of histamine 1 receptor had no effects on the circadian rhythm of spontaneous locomotion, but the knockout of the histamine 3 receptor resulted in a substantial reduction of free-running activity rhythm amplitude. The expressions of the core clock genes, Per1, Per2 and Bmal1, in the suprachiasmatic nuclei of the hypothalamus, the cerebral cortex and the striatum were not affected in these knockout models. Based on the acquired results we concluded that the circadian process may affect homeostatic regulation, thus indicating an interaction of these processes. The circadian regulation of the histaminergic neurons takes place mainly at the level of histamine accumulation and release. In contrast, alterations in histamine-mediated signal transduction caused only minor alterations in examined circadian rhythms. Finally, we could not find evidence of an involvement of the histamine in homeostatic regulation of sleep-wakefulness cycle.

KW - Brain

KW - +physiology

KW - Biological Clocks

KW - Cerebral Cortex

KW - +drug effects

KW - Cholinergic Neurons

KW - Circadian Rhythm

KW - Dose-Response Relationship, Drug

KW - Electroencephalography

KW - Electromyography

KW - Histamine

KW - +metabolism

KW - Histamine Agonists

KW - Histamine Antagonists

KW - Histamine Release

KW - Hypothalamus

KW - Prosencephalon

KW - Sleep Deprivation

KW - +physiopathology

KW - Sleep Stages

KW - Time Factors

KW - Wakefulness

KW - 3112 Neurosciences

KW - 3111 Biomedicine

M3 - Doctoral Thesis

SN - 978-951-51-2135-6

T3 - Dissertationes Scholae Doctoralis Ad Sanitatem Investigandam Universitatis Helsinkiensis

PB - University of Helsinki

CY - Helsinki

ER -

Rozov S. Circadian and histaminergic regulation of the sleep-wakefulness cycle. Helsinki : University of Helsinki, 2016. 69 p. (Dissertationes Scholae Doctoralis Ad Sanitatem Investigandam Universitatis Helsinkiensis; 33/2016 ).