The circadian timing system is highly integrated with the sleep-wake regulation system. This thesis focuses on how different pharmacological treatments influence the sleep regulation system and the... Show moreThe circadian timing system is highly integrated with the sleep-wake regulation system. This thesis focuses on how different pharmacological treatments influence the sleep regulation system and the circadian timing rhythm in two murine models. In the first animal model, which is presented in Chapter 2 and 3, we implanted EEG/EMG electrodes in freely moving Brown Norway rats. We chose this rat strain because it is pigmented and therefore a more representative model than the more mainstream rat strains which are usually albino rats. This study aimed to investigate the effect of caffeine, sleep deprivation and ketamine on sleep and circadian-controlled activity under constant darkness. In the second animal model, which is presented in Chapter 4 and 5, we implanted EEG/EMG or Multi-unit electrodes in chemotherapy-induced fatigue mice. All the results from this thesis and future perspectives were discussed in Chapter 6. We are able to see how disruption of sleep and the circadian clock adversely affect health and may contribute to many diseases in modern society. In this thesis, these studies provide a better understanding of these drugs influence the circadian timing system and sleep-wake regulation and maybe new treatment approaches for antidepressant therapy and cancer related fatigue. Show less
Most organisms on Earth anticipate changes between day and night using an internal biological clock. This clock is localized in a small brain area: the suprachiasmatic nucleus (SCN). The SCN... Show moreMost organisms on Earth anticipate changes between day and night using an internal biological clock. This clock is localized in a small brain area: the suprachiasmatic nucleus (SCN). The SCN generates rhythms of approximately 24 hours (circadian) which are synchronized to light. We investigated how light signals reach the SCN and how the effects of light and behavioural activity on the SCN differ between diurnal and nocturnal species. In this thesis, we show that cone photoreceptors, involved in colour vision, contribute to the light responses of the circadian clock. As observed in fMRI experiments, the human SCN was also sensitive to different colours of light. Furthermore, the SCN of diurnal species was partly inhibited by light, whereas the SCN of nocturnal species was mostly excited. Finally, we observed that behavioural activity activates the SCN of diurnal species, whereas in nocturnal species the SCN is inhibited. We concluded that the input pathways to the circadian clock differ between diurnal and nocturnal species and hypothesize that these differences could contribute to the temporal activity profiles. Together, our findings facilitate the translation of circadian research from nocturnal laboratory animals to diurnal humans, for the benefit of biological rhythms and health in general. Show less
In mammals, an endogenous clock located in the suprachiasmatic nucleus (SCN), synchronizes physiological and biological rhythms to the environmental light–dark cycle. In experiments, most... Show moreIn mammals, an endogenous clock located in the suprachiasmatic nucleus (SCN), synchronizes physiological and biological rhythms to the environmental light–dark cycle. In experiments, most researchers applied rectangular scheme as the external light–dark scheme received by the SCN neuronal oscillators. However, the external light intensity changes gradually throughout the day. Therefore, trapezoidal schemes (twilight) or sinusoidal schemes were also applied. Thus far, the effects of different light–dark schemes on the oscillators of the SCN did not get fully explored. In the present study, we theoretically analyzed how the five common light–dark schemes affect the entrainment ability of the SCN, based on a Poincaré model. We numerically found that when the maximum light intensity, the minimum light intensity, and the total amount of light exposure per cycle were the same, the largest entrainment range was obtained in the oscillators receiving more light in the daytime. However if, under the condition of 12:12-h illumination, the total amount of light exposure per cycle was the same, the maximum light intensity during the day leaded to an increased range of entrainment. Moreover, the entrainment range was reduced when the photoperiod was extended. Note that, increasing the maximum light intensity increased the entrainment ability of all light–dark schemes. Our results exposes the important role of light–dark schemes in the entrainment ability of the SCN network, and provides a potential explanation for the diversity of the entrainment range between diurnal and nocturnal animals. Show less
Cardiovascular diseases (CVD) are the leading mortality cause. Its largest underlying issue is atherosclerosis: arterial narrowing due to the buildup of cholesterol, lipids, and immune cells. High... Show moreCardiovascular diseases (CVD) are the leading mortality cause. Its largest underlying issue is atherosclerosis: arterial narrowing due to the buildup of cholesterol, lipids, and immune cells. High blood pressure and cholesterol levels are well-known risk factors. Despite the effectiveness of currently-available medication to improve these factors, a considerable residual risk remains, indicating the importance of other risk factors, such as age and sex. Women have a lower risk of developing CVD than men at a young age, which reverses at older age. CVD are also more common among night shift workers. The research described in this thesis used mouse models to provide new insight in the interplay between sex, age, and disturbances in day and night rhythms in atherosclerosis development, and emphasize the importance of including both men and women in scientific studies. Brown fat is one of the tissues adversely affected by disturbances in day and night rhythms and aging, and the ANGPTL4 protein was identified as an important regulator of brown fat. Inhibiting ANGPTL4 production selectively in liver cells appears a safe and promising therapeutic strategy to combat atherosclerosis. The findings also imply that time-restricted eating could be an effective tool in lowering CVD risk in shift workers. Show less
Cancer-related fatigue is one of the most frequently reported symptoms after treatment for (non-)Hodgkin lymphoma. This dissertation describes the procedure and results of the SPARKLE trial which... Show moreCancer-related fatigue is one of the most frequently reported symptoms after treatment for (non-)Hodgkin lymphoma. This dissertation describes the procedure and results of the SPARKLE trial which primarily aimed to investigate whether light therapy can be used as a treatment for chronic cancer-related fatigue since the diagnosis of Hodgkin lymphoma or diffuse large B-cell lymphoma. Secondary aims included the investigating of the effect of light therapy on symptoms related to cancer-related fatigue, for example depression, anxiety, quality of life, sleep quality, cognitive complaints and cognitive functioning. Objective measurements of the sleep-wake cycle (assessed with actigraphy) and circadian rhythms (melatonin and cortisol from saliva) were also included. An additional chapter describes the psychometric evaluation of the Multidimensional Fatigue Inventory. This questionnaire was one of the primary outcomes of the SPARKLE trial. The final chapter describes a critical evaluation of the results of the SPARKLE trial compared to the current literature, offers clinical implications and proposals for future research. Show less
The premonitory phase and early phase of both spontaneous and nitroglycerin-triggered migraine attacks were explored in this thesis, in association with clinical modulators and trigger factors.... Show moreThe premonitory phase and early phase of both spontaneous and nitroglycerin-triggered migraine attacks were explored in this thesis, in association with clinical modulators and trigger factors. Clinical research strategies, experimental designs, neuroimaging techniques and biochemical methods have revealed clinical risk factors, biochemical modulators and pharmacological triggers. Furthermore, newly discovered hypothalamus-specific alterations in metabolism and perfusion in the early phases of the migraine attack were described. Taken together, these results suggest that each migraine attack starts well before the initiation of the headache phase. The hypothalamus is postulated to have a pivotal role in the early phases of the migraine attack, and possibly affects attack susceptibility interictally as well. Show less
Aims/hypothesisAnimal studies have indicated that disturbed diurnal rhythms of clock gene expression in adipose tissue can induce obesity and type 2 diabetes. The importance of the circadian timing... Show moreAims/hypothesisAnimal studies have indicated that disturbed diurnal rhythms of clock gene expression in adipose tissue can induce obesity and type 2 diabetes. The importance of the circadian timing system for energy metabolism is well established, but little is known about the diurnal regulation of (clock) gene expression in obese individuals with type 2 diabetes. In this study we aimed to identify key disturbances in the diurnal rhythms of the white adipose tissue transcriptome in obese individuals with type 2 diabetes.MethodsIn a case-control design, we included six obese individuals with type 2 diabetes and six healthy, lean control individuals. All participants were provided with three identical meals per day for 3days at zeitgeber time (ZT, with ZT 0:00 representing the time of lights on) 0:30, 6:00 and 11:30. Four sequential subcutaneous abdominal adipose tissue samples were obtained, on day 2 at ZT 15:30, and on day 3 at ZT 0:15, ZT 5:45 and ZT 11:15. Gene expression was measured using RNA sequencing.ResultsThe core clock genes showed reduced amplitude oscillations in the individuals with type 2 diabetes compared with the healthy control individuals. Moreover, in individuals with type 2 diabetes, only 1.8% (303 genes) of 16,818 expressed genes showed significant diurnal rhythmicity, compared with 8.4% (1421 genes) in healthy control individuals. Enrichment analysis revealed a loss of rhythm in individuals with type 2 diabetes of canonical metabolic pathways involved in the regulation of lipolysis. Enrichment analysis of genes with an altered mesor in individuals with type 2 diabetes showed decreased activity of the translation initiating pathway EIF2 signaling'. Individuals with type 2 diabetes showed a reduced diurnal rhythm in postprandial glucose concentrations.Conclusions/interpretationDiurnal clock and metabolic gene expression rhythms are decreased in subcutaneous adipose tissue of obese individuals with type 2 diabetes compared with lean control participants. Future investigation is needed to explore potential treatment targets as identified by our study, including clock enhancement and induction of EIF2 signalling.Data availabilityThe raw sequencing data and supplementary files for rhythmic expression analysis and Ingenuity Pathway Analysis have been deposited in NCBI Gene Expression Omnibus (GEO series accession number GSE104674). Show less
In order to cope with and to predict 24-hour rhythms in the environment, most, if not all, organisms have a circadian timing system. The most important mammalian circadian pacemaker is located in... Show moreIn order to cope with and to predict 24-hour rhythms in the environment, most, if not all, organisms have a circadian timing system. The most important mammalian circadian pacemaker is located in the suprachiasmatic nucleus at the base of the hypothalamus in the brain. Over the years, it has become clear that the circadian system is complex and that additional oscillators exist, both within and outside the central nervous system. The aim of this thesis was to obtain insight in the hierarchical organization of the circadian timing system and to determine whether certain attributes arise at the tissue level. The data reveal that interactions between the SCN and the periphery, as well as interactions between subregions within the SCN, contribute significantly to the functioning of the circadian system. Another important finding is that the multiple components of the circadian system can, under certain circumstances, dissociate. The hierarchical organization of the circadian timing system, the interactions between and within organizational levels, and importantly, the ability of several components to dissociate, may provide the circadian system the required plasticity to adjust to biologically relevant changes in the environment. Show less
