Evolutionary most species have developed internal clocks, enabling them to optimally coordinate their physiology and behavior with the local environment. In mammals, the suprachiasmatic nucleus ... Show moreEvolutionary most species have developed internal clocks, enabling them to optimally coordinate their physiology and behavior with the local environment. In mammals, the suprachiasmatic nucleus (SCN) serves as the master clock of the body and is located in the hypothalamus in the brain. Circadian rhythms in electrical activity function as output of the SCN and are generated by the complex interplay between SCN neurons. The research in this thesis aimed at identifying network properties of the circadian clock by investigating the four functional components of the SCN: (1) light input to the SCN, (2) neural network synchronization within the SCN, (3) output from the SCN to brain and body, and (4) feedback from these processes back to the SCN. We used empirical data together with computational methods to obtain new insights in the network properties of the circadian clock. We furthermore identified similarities and differences in the SCN network between nocturnal and diurnal species. As there are many diseases affecting clock function, understanding the SCN network is a first step towards maintaining health. Show less
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
Leeuw, M. de; Verhoeve, S.I.; Wee, N.J.A. van der; Hemert, A.M. van; Vreugdenhil, E.; Coomans, C.P. 2023
Circadian rhythms have evolved in almost all organisms enabling them to anticipate alternating changes in the environment. As a consequence, the circadian clock controls a broad range of bodily... Show moreCircadian rhythms have evolved in almost all organisms enabling them to anticipate alternating changes in the environment. As a consequence, the circadian clock controls a broad range of bodily functions including appetite, sleep, activity and cortisol levels. The circadian clock synchronizes itself to the external world mainly by environmental light cues and can be disturbed by a variety of factors, including shift-work, jet-lag, stress, ageing and artificial light at night.Interestingly, mood has also been shown to follow a diurnal rhythm. Moreover, circadian disruption has been associated with various mood disorders and patients suffering from depression have irregular biological rhythms in sleep, appetite, activity and cortisol levels suggesting that circadian rhythmicity is crucially involved in the etiology and pathophysiology of depression.The aim of the present review is to give an overview and discuss recent findings in both humans and rodents linking a disturbed circadian rhythm to depression. Understanding the relation between a disturbed circadian rhythm and the etiology of depression may lead to novel therapeutic and preventative strategies. 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
The experimental research in this thesis aims to gain more understanding of how the SCN network is organized and what is needed for network changes. More specifically, this work focused on the... Show moreThe experimental research in this thesis aims to gain more understanding of how the SCN network is organized and what is needed for network changes. More specifically, this work focused on the potential role of GABA and the GABAeric E/I balance in SCN network plasticity. Communication and synchronization in the SCN are important for the generation of a strong and coherent output signal. Under certain conditions, like long photoperiod, the phases of the individual SCN cells are more dispersed over the 24 hour cycle as evidenced by measurements of electrical activity and clock gene expression. Aging is also known to affect the network organization of the SCN with deterioration in synchronization among the individual SCN neurons. In this thesis, I present work that contributes to research questions regarding the effect of light exposure and/or aging on several characteristics of SCN network plasticity. Show less
Buijink, M.R.; Weeghel, M. van; Gulersonmez, M.C.; Harms, A.C.; Rohling, J.H.T.; Meijer, J.H.; ... ; Michel, S. 2018
In this thesis, we explored pituitary functioning and extra-pituitary implications of two pituitary disorders in humans. In part A, we focused on the long-term consequences of the diagnosis and... Show moreIn this thesis, we explored pituitary functioning and extra-pituitary implications of two pituitary disorders in humans. In part A, we focused on the long-term consequences of the diagnosis and treatment of nonfunctioning pituitary macroadenoma (NFMA) on hypothalamic regulation of circadian rhythmicity. These patients are at theoretical risk for damage of especially the hypothalamic suprachiasmatic nucleus (SCN), harboring the seat of the body’s central clock, and its projections. The studies aimed to explore symptoms of SCN dysfunctioning and their implications for patients, in order to formulate strategies to prevent or manage these long-term disabilities. In part B, we focused on the clinical characteristics and pathophysiology of the X-linked IGSF1 deficiency syndrome, in order to aid physicians in providing the necessary diagnostic procedures and long-term care for these patients, and to learn about IGSF1’s role in endocrine physiology. Show less
Motor disturbances, cognitive decline and psychiatric symptoms are considered as the key symptoms of Huntington__s disease (HD). Yet, other prevalent features include unintended weight loss, sleep... Show moreMotor disturbances, cognitive decline and psychiatric symptoms are considered as the key symptoms of Huntington__s disease (HD). Yet, other prevalent features include unintended weight loss, sleep and circadian disturbances and autonomic nervous system dysfunction. The nature of these features supports a pivotal role of the hypothalamus in the HD disease process. In this thesis data is presented from immunocytochemical and in situ hybridization studies demonstrating substantial pathology in hypothalamic neuropeptide expression in HD patients. Main findings include neuropeptide changes in the suprachiasmatic nucleus, the body__s master clock, that will likely be responsible for disruption of 24h circadian rhythmicity. Secondly, the neuronal histaminergic system is hyperactive at both the level of the hypothalamic tuberomamillary nucleus as well as in the cerebral neocortex. These changes could partly explain weight loss and cognitive decline in patients. The expression of neuropeptides in the hypothalamic paraventricular and infundibular nuclei, however, seems to be relatively unaffected by the HD disease process. Finally, a discrepancy between mRNA expression and protein expression of many hypothalamic neuropeptides was observed that can be partly explained by a decrease of prohormone convertase expression. Interestingly, hypothalamic changes in existing HD transgenic rodent models are largely non-representative of hypothalamic changes in HD patients. Show less
The biological clock regulates daily and seasonal rhythms in mammals. This clock is located in the suprachiasmatic nuclei (SCN), which are two small nuclei each consisting of 10,000 neurons. The... Show moreThe biological clock regulates daily and seasonal rhythms in mammals. This clock is located in the suprachiasmatic nuclei (SCN), which are two small nuclei each consisting of 10,000 neurons. The neurons of the SCN endogenously generate a rhythm of approximately 24 hours. Under the influence of the light-dark cycle, the SCN produce a coordinated output that is subjected to daily environmental changes. The adaptation to the light-dark cycle is a property of the neuronal network of the SCN. This neuronal network also explains the adjustment to long summer days and short winter days, and to shifts in the light-dark cycle caused by transatlantic flights or shift work. In this thesis the neuronal network of the SCN is investigated using computational techniques. The computer simulations were directed by experimental results, while, vice versa, new experiments were guided by results from the simulations. These coordinated efforts of computational science and life sciences show how properties emerge at the neuronal network level, that are not present in individual cells. 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
