Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 5 uppsatser.

Thesis (M.Sc.). / Written for the Département de Neurologie et Neurochirurgie. Title from title page of PDF (viewed 2009/09/07). Includes bibliographical references.

Thesis (doctoral)--Ludwig Maximilians-Universität zu München, 1979.

Daily rhythms of physiology and behaviour in mammals are orchestrated by a hierarchical network of cellular oscillators. The master pacemaker that defines local and systemic timing across the brain and body are the suprachiasmatic nuclei of the hypothalamus (SCN). Disruption to the timing of sleep and daily behavioural activity can manifest in a range of pathologies including neuropsychiatric disorders. Bipolar disorder (BPD) is once such neurological condition that exhibits profound associations with altered circadian rhythm generation and whose toolkit of pharmacological interventions impact upon circadian rhythm generation. Currently it is unclear exactly how changes to rhythmic physiology contribute to the aetiology and pathology of BPD. In recent years, rodent models possessing lesions within genes that make up the basic cellular oscillator are widely reported to exhibit concomitant changes in affective behaviours, namely mania-like phenotypes. Recently a mouse model possessing a mutation within the neuron-specific Na+/K+-ATPase (NKA) alpha3 subunit, known as Myshkin, was described as a model of the manic phase of BPD. The NKA alpha3 is not reported as a critical element of the circadian oscillator and we used this opportunity to characterise the behavioural and physiological circadian system of these animals. Under wheel-running paradigms Myk/+ animals exhibited a broad array of behavioural deficits including lengthened, low amplitude and labile free-running rhythms, altered phase re-setting and elevated metabolic activity. Physiological characterisation of the SCN revealed deficits in amplitude of electrical output and changes to post-synaptic signalling although the ex vivo molecular pacemaking of the SCN remained intact. Myshkin animals therefore represent a novel model in which changes to central output arise independently of changes to basic molecular pacemaking. Despite this seemingly distinct mechanism Myshkin animals share many mood and circadian phenotypes with other clock gene models of affective behaviours highlighting that changes to pacemaking output of the SCN may be a critical factor across animal models exhibiting circadian and mood deficits. In addition, the impact of the mood stabiliser lithium, commonly prescribed in BPD, on cellular pathways within the SCN was investigated. Lithium consistently lengthens the period of cellular and behavioural rhythms in mammals although the mechanism of this action is yet undefined. Glycogen synthase kinase 3β (GSK3β) and inositol monophosphatase (IMPase) are the major biochemical targets of lithium at therapeutic concentrations. GSK3β is known to shorten rhythms and this study targeted IMPase and inositol phosphate turnover in the period lengthening effects of lithium. We reveal that although inhibition of IMPase dampens SCN molecular rhythms, the period of oscillations remains unchanged and therefore lithium acts upon distinct cellular pathways within the SCN to exert effects on period.

Almost all organisms have approximately a 24-hour circadian rhythm that enables them to anticipate their environment’s daily rhythmicity. Anticipation increases their likelihood of success in foraging, reproduction, predation, and other life events. Therefore, a disruption of their endogenous clock results in detrimental physiological consequences that significantly impact organisms’ fitness. Surprisingly, we have found numerous spider species with free-running periods that deviate greatly from 24 hours. Free-running period (FRP) is a standard measurement of the period of an organism’s circadian rhythm found by measuring periodicity of behaviors or physiology under constant conditions (e.g., constant darkness and temperature). So far, these extreme spider FRPs have only been observed in the superfamily Araneoidea, but we have only limited sampling of species outside this clade. Therefore, we want to fill this data gap of non-araneoid spiders to deepen our understanding of the evolution of circadian clocks in spiders. Also, we will observe if significant deviation from 24 hours and wide variation in FRP are common to all spider species or are only characteristics of araneoid spiders. Here, we describe the FRPs of four non-araneoid spider species belonging to the RTA clade: Schizocosa avida, Phidippus audax, Agelenopsis pennsylvanica, and Mecaphesa celer. We detected significant free runs (mean + SD) at p<0.001 using Lomb-Scargle periodograms in three out of the four species: S. avida (23.84 ± 1.03 h); P. audax (22.67 ± 0.36 h); and A. pennsylvanica (23.97 ± 0.32 h). However, M. celer was found to be arrhythmic under constant conditions. These findings of near 24-hour FRPs with low deviation among the RTA species, along with previous data, strongly suggest that extreme FRPs are confined to the Araneoidea clade. Thus, we have phylogenetically localized a major evolutionary change in the circadian system of spiders occurring in the Araneoidea clade, approximately 170 million years ago.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21255号 / 医博第4373号 / 新制||医||1029(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 長船 健二, 教授 柳田 素子, 教授 渡邊 直樹 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

No description available.

Circadian rhythms are nearly ubiquitous and are responsible for timing biological processes and allowing for anticipation of regular changes in the environment. The internal clocks of most organisms have a period very close to 24 hours with little variation. Spiders, however, do not seem to follow this pattern. Both the fastest (18 hours) and slowest (29 hours) naturally-occurring clocks are found in spiders, and variation within a species can be orders of magnitude larger than that of previously studied animals. Circadian rhythms are assumed to be adaptive, yet little is known about their heritability in arthropods. Heritability is defined as the amount of phenotypic variation that can be attributed to genetic variation passed down from parent to offspring. Phenotype can be influenced by many complex factors including environmental effects, dominance of genetic sequences, and gene interactions. Because of these influences, the phenotypic characteristics of an individual can vary greatly, and it is often difficult to precisely identify what is truly heritable. Using spiders as a model system, we can exploit the extreme variation in circadian rhythms to investigate the potential contribution from heritability. Strong heritability would suggest that wide variation in circadian rhythms likely reflects high genetic variability in the species. Alternatively, the environment may have a greater contribution in this variation relative to the effects of heritability. To test this, we chose Parasteatoda tepidariorum, a common cobweb spider with a relatively short circadian period of 21.7 hours and intraspecific variation of more than 4 hours. To estimate the heritability of circadian rhythm, adult females were gathered with accompanying egg cases, and juveniles were raised from those cases. Six fundamental parameters of circadian rhythms were measured from the locomotor activity of adults and juveniles. Of those six, only one parameter differed between adults and juveniles: the onset of locomotor activity during the first five days when light cycles were present (Mann-Whitney U= 1814, p= 0.04). When all six circadian parameters were compared by regression of adults to respective offspring, none showed significant correlation. This indicates that variation in circadian rhythms was likely not caused by parental genetics, and that environmental factors, such as artificial light at night, may be the source of the extreme circadian rhythms seen in spiders. Another possible cause for this variation may be the presence of weak molecular circadian oscillators that are more sensitive to environmental factors than those in most other circadian systems.

Circadian rhythms are outputs of the internal clock that regulates the daily functions of almost all living organisms. Circadian rhythms are typically 24 hours because they are synchronized by external cues such as the natural light/dark cycles of the environment. When external cues are removed, the circadian rhythm “free-runs,” thus revealing the organism’s endogenous circadian period. Recent studies have found that the trashline orbweaving spiders Cyclosa turbinata and Allocyclosa bifurca have abnormally short circadian rhythms of approximately 19 and 18 hours, respectively. Trashline orbweavers construct a line of debris made of prey carcasses in the center of their web and then remain undetectable by being cryptic within their trashline. Despite similar circadian rhythms and web-building behaviors, recent genetic findings indicate that these species actually are not closely related. In fact, both genetic and morphological data now suggest A. bifurca is more closely related to Cyrtophora citricola, the Tropical Tent-web spider. This would suggest that trashline behavior and exceptionally short circadian clocks evolved independently in C. turbinataand A. bifurca. This study analyzed the circadian rhythm of C. citricola and compared it to the circadian rhythm of A. bifurca. If C. citricola has an abnormally short clock like A. bifurca, this would indicate that the evolution of the short clock preceded the divergence of these species’ lineages. However, if C. citricola has a more typical clock, this would suggest that the unusually short clock evolved in the A. bifurca lineage and may be more ecologically linked to the trashline behavior. Thirty-two female C. citricola were collected in Southern Florida and had their locomotor activity measured over four days of 12:12 light/dark cycles followed by complete darkness to determine their circadian free-running periods (FRP). Cyrtophora citricola was found to have a more typical FRP of 24.0 + 0.43 hours. Despite being closely related, C. citricola and A. bifurca differ significantly in their circadian rhythms, suggesting that short circadian rhythms may be ecologically linked with trashline behavior.

This study creates and analyzes a model of the Hypothalamus-Pituitary-Adrenal axis to better understand cortisol rhythmicity perpetuated by circadian inputs, system dynamics and feedback inherent within the system. Differential equations are created to model human physiology with cortisol and precursor hormone outputs fit to physiologic data. The model is created with an input of circadian cues from the hypothalamus which are designed to create a more realistic stimulation of the cortisol cascade over predecessors. The study also incorporates additional signaling pathways unique to this model. The project explores the properties of the model under mathematical analysis; then, the simulation of known medical pathologies is used to analyze the model's predictive ability. It is found that incorporating the additional signaling pathway of Arginine Vasopressin increases the model's predictive capability in certain pathological conditions over predecessor models. Additionally, the origination of ultradian rhythm is explored through simulation and two possible explanations are found. First, pulsatile release of Adrenocorticotropic Hormone combined with negative feedback into the system from glucocorticoid receptors elicits the observed ultradian oscillations in humans. Additionally, simulations of increased hypothalamic monitoring and control of cortisol concentrations create a natural oscillation within the desired period. Results from numerical perturbation simulations and dynamic sensitivity analysis are employed to offer justification for known pathological conditions developing from circadian dysregulation. / Master of Science / This study aims to better understand the body's natural cortisol rhythm by creating a mathematical model of the Hypothalamus-Pituitary-Adrenal axis. The model uses differential equations to simulate human physiology and includes circadian cues from the suprachiasmatic nucleus to create a more accurate representation of how cortisol is released in the body. The study also incorporates additional signaling pathways and interactions unique to this model. By analyzing the model and simulating known medical conditions, it was found found that incorporating these additional signaling pathways improved the model's predictive ability in certain situations. Then, numerical simulations were used to investigate how circadian dysregulation can lead to pathological conditions.The study also explored the origin of ultradian rhythm, or short-term fluctuations in cortisol levels, and found two possible explanations. One explanation is the pulsatile release of Adrenocorticotropic Hormone combined with negative feedback from glucocorticoid receptors. Another explanation is increased hypothalamic control of cortisol concentrations. Overall, this study provides insights into the complex dynamics of the Hypothalamus-Pituitary-Adrenal axis and the origination of pathology in the system.