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Buijs, Ruud M.; Scheer, Frank A.; Kreier, Felix; Yi, Chunxia; Bos, Nico; Goncharuk, Valeri D.; Kalsbeek, Andries(2006): Organization of circadian functions: interaction with the body. In: Progress in brain research, Jg. 153, S.

341–360. Online verfügbar unter doi:10.1016/S0079-6123(06)53020-1.

Abstract The hypothalamus integrates information from the brain and the body; this activity isessential for survival of the individual (adaptation to the environment) and thespecies (reproduction). As a result, countless functions are regulated byneuroendocrine and autonomic hypothalamic processes in concert with theappropriate behaviour that is mediated by neuronal influences on other brain areas.In the current chapter attention will be focussed on fundamental hypothalamicsystems that control metabolism, circulation and the immune system. Herein asystem is defined as a physiological and anatomical functional unit, responsible forthe organisation of one of these functions. Interestingly probably because thesesystems are essential for survival, their function is highly dependent on each other'sperformance and often shares same hypothalamic structures. The functioning ofthese systems is strongly influenced by (environmental) factors such as the time ofthe day, stress and sensory autonomic feedback and by circulating hormones. Inorder to get insight in the mechanisms of hypothalamic integration we havefocussed on the influence of the biological clock; the suprachiasmatic nucleus(SCN) on processes that are organized by and in the hypothalamus. The SCNimposes its rhythm onto the body via three different routes of communication: 1.Viathe secretion of hormones; 2. via the parasympathetic and 3.via the sympatheticautonomous nervous system. The SCN uses separate connections via either thesympathetic or via the parasympathetic system not only to prepare the body for thecoming change in activity cycle but also to prepare the body and its organs for thehormones that are associated with such change. Up till now relatively little attentionhas been given to the question how peripheral information might be transmittedback to the SCN. Apart from light and melatonin little is known about other systemsfrom the periphery that may provide information to the SCN. In this chapter attentionwill be paid to e.g. the role of the circumventricular organs in passing info to theSCN. Herein especially the role of the arcuate nucleus (ARC) will be highlighted.The ARC is crucial in the maintenance of energy homeostasis as an integrator oflong- and short-term hunger and satiety signals. Receptors for metabolic hormoneslike insulin, leptin and ghrelin allow the ARC to sense information from the peripheryand signal it to the central nervous system. Neuroanatomical tracing studies usinginjections of a retrograde and anterograde tracer into the ARC and SCN showed areciprocal connection between the ARC and the SCN which is used to transmitfeeding related signals to the SCN. The implications of multiple inputs and outputsof the SCN to the body will be discussed in relation with metabolic functions.Schlagwörter Animals; Autonomic Pathwaysphysiology; Biological Clocksphysiology; CircadianRhythmphysiology; Endocrine Systemphysiology; Humans;Hypothalamuscytologyphysiology; Neuronsphysiology; NeuropeptidesmetabolismHu, K.; Scheer, F. A. J. L.; Ivanov, P. Ch; Buijs, R. M.; Shea, S. A. (2007): The suprachiasmatic nucleus

functions beyond circadian rhythm generation. In: Neuroscience, Jg. 149, H. 3, S. 508–517. Online verfügbar

unter doi:10.1016/j.neuroscience.2007.03.058.Abstract We recently discovered that human activity possesses a complex temporalorganization characterized by scale-invariant/self-similar fluctuations from secondsto approximately 4 h-(statistical properties of fluctuations remain the same atdifferent time scales). Here, we show that scale-invariant activity patterns areessentially identical in humans and rats, and exist for up to approximately 24 h: six-times longer than previously reported. Theoretically, such scale-invariant patternscan be produced by a neural network of interacting control nodes-systemcomponents with feedback loops-operating at different time scales. However suchcontrol nodes have not yet been identified in any neurophysiological model of scaleinvariance/self-similarity in mammals. Here we demonstrate that the endogenous

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circadian pacemaker (suprachiasmatic nucleus; SCN), known to modulatelocomotor activity with a periodicity of approximately 24 h, also acts as a majorneural control node responsible for the generation of scale-invariant locomotorpatterns over a broad range of time scales from minutes to at least 24 h (rather thansolely at approximately 24 h). Remarkably, we found that SCN lesion in ratscompletely abolished the scale-invariant locomotor patterns between 4 and 24 hand significantly altered the patterns at time scales <4 h. Identification of the controlnodes of a neural network responsible for scale invariance is the critical first step inunderstanding the neurophysiological origin of scale invariance/self-similarity.Schlagwörter Activity Cyclesphysiology; Adult; Animals; Circadian Rhythmphysiology; Darkness;Data Interpretation, Statistical; Female; Humans; Light; Male; MotorActivityphysiology; Rats; Rats, Wistar; Suprachiasmatic NucleusphysiologyHu, Kun; Scheer, Frank A. J. L.; Buijs, Ruud M.; Shea, Steven A. (2008): The endogenous circadian pacemakerimparts a scale-invariant pattern of heart rate fluctuations across time scales spanning minutes to 24 hours. In:

Journal of biological rhythms, Jg. 23, H. 3, S. 265–273. Online verfügbar unter doi:10.1177/0748730408316166.

Abstract Heartbeat fluctuations in mammals display a robust temporal structurecharacterized by scale-invariant/fractal patterns. These scale-invariant patternslikely confer physiological advantage because they change with cardiovasculardisease and these changes are associated with reduced survival. Models ofphysical systems imply that to produce scale-invariant patterns, factors influencingthe system at different time scales must be coupled via a network of feedbackinteractions. A similar cardiac control network is hypothesized to be responsible forthe scale-invariant pattern in heartbeat dynamics, although the essential networkcomponents have not been determined. Here is shown that scale-invariant cardiaccontrol occurs across time scales from minutes to approximately 24 h, and thatlesioning the mammalian circadian pacemaker (suprachiasmatic nucleus; SCN)completely abolishes the scale-invariant pattern at time scales>or approximately 4h. At time scales<or approximately 4 h, the scale invariance persisted followingSCN lesion but with a different pattern. These results indicate previouslyunrecognized multiscale influences of the SCN on heart rate fluctuations thatcannot be explained by a simple pacemaker of 24-h rhythmicity. The conclusion isthat the SCN serves as a major node in the cardiac control network and impartsscale-invariant cardiac control across a wide range of time scales with strongesteffects between approximately 4 and 24 h. These results demonstrate thatexperimental manipulations (e.g., SCN lesion) can be used to begin to model andunderstand the origin of scale-invariant behavior in a neurophysiological system.Schlagwörter Animals; Biological Clocks; Circadian Rhythm; Heart Rate; Rats; Rats, Wistar;Suprachiasmatic NucleusphysiologyHu, Kun; Scheer, Frank A. J. L.; Buijs, Ruud M.; Shea, Steven A. (2008): The circadian pacemaker generatessimilar circadian rhythms in the fractal structure of heart rate in humans and rats. In: Cardiovascular research,

Jg. 80, H. 1, S. 62–68. Online verfügbar unter doi:10.1093/cvr/cvn150.

Abstract AIMS: Adverse cardiovascular events in humans occur with a day/night pattern,presumably related to a daily pattern of behaviours or endogenous circadianrhythms in cardiovascular variables. Healthy humans possess a scale-invariant/fractal structure in heartbeat fluctuations that exhibits an endogenouscircadian rhythm and changes towards the structure observed in cardiovasculardisease at the circadian phase corresponding to the time of the broad peak ofadverse cardiovascular events (at about 10 AM). To explore the relationshipbetween the rest/activity cycle, endogenous circadian rhythmicity, and cardiacvulnerability, we tested whether the fractal structure of heart rate exhibits a similarcircadian rhythm in a mammalian species that is nocturnally active (Wistar rats)compared with diurnally active humans, and how this fractal structure changes afterlesioning the circadian pacemaker (suprachiasmatic nucleus, SCN) in rats.METHODS AND RESULTS: Analysis of heart rate data collected over 10 days in

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eight intact and six SCN-lesioned Wistar rats during constant darkness revealedthat: (i) as with humans, rats exhibit an endogenous circadian rhythm in the scalingexponent characterizing the hourly fractal structure of heart rate (P = 0.0005) withlarger exponents during the biological day (inactive phase for rats; active phase forhumans); (ii) SCN lesioning abolished the rhythm in the fractal structure of heartrate and systematically increased the scaling exponent (P = 0.01). CONCLUSION:Rats possess a circadian rhythm of fractal structure of heart rate with a similartemporal pattern as previously observed in humans despite opposite rest/activitycycles between the two species. The SCN imparts this endogenous rhythm.Moreover, lesioning the SCN in rats results in a larger scaling exponent, as occurswith cardiovascular disease in humans.Schlagwörter Animals; Biological Clocks; Circadian Rhythm; Fractals; Heart Rate; Humans; Rats;Rats, Wistar; Suprachiasmatic NucleusphysiologyKalsbeek, A.; Palm, I. F.; La Fleur, S. E.; Scheer, F. A. J. L.; Perreau-Lenz, S.; Ruiter, M. et al. (2006): SCN

outputs and the hypothalamic balance of life. In: Journal of biological rhythms, Jg. 21, H. 6, S. 458–469. Online

verfügbar unter doi:10.1177/0748730406293854.Abstract The circadian clock in the suprachiasmatic nucleus (SCN) is composed ofthousands of oscillator neurons, each dependent on the cell-autonomous action of adefined set of circadian clock genes. Still, the major question remains how theseindividual oscillators are organized into a biological clock producing a coherentoutput able to time all the different daily changes in behavior and physiology. In thepresent review, the authors discuss the anatomical connections andneurotransmitters used by the SCN to control the daily rhythms in hormone release.The efferent SCN projections mainly target neurons in the medial hypothalamussurrounding the SCN. The activity of these preautonomic and neuroendocrine targetneurons is controlled by differentially timed waves of, among others, vasopressin,GABA, and glutamate release from SCN terminals. Together, the data on the SCNcontrol of neuroendocrine rhythms provide clear evidence not only that the SCNconsists of phenotypically (i.e., according to neurotransmitter content) differentsubpopulations of neurons but also that subpopulations should be distinguished(within phenotypically similar groups of neurons) based on the acrophase of their(electrical) activity. Moreover, the specialization of the SCN may go as far as asingle body structure, that is, the SCN seems to contain neurons that specificallytarget the liver, pineal, and adrenal.SchlagwörterAnimals; Autonomic Nervous Systemphysiology; Biological Clocksphysiology;Circadian Rhythmphysiology; Humans; Neuronsphysiology; SuprachiasmaticNucleusphysiologysecretion; VasopressinsphysiologyScheer, F. A.; Buijs, R. M. (1999): Light affects morning salivary cortisol in humans. In: The Journal of clinical

endocrinology and metabolism, Jg. 84, H. 9, S. 3395–3398.

Abstract The effect of light on the morning-cortisol peak in humans was investigated infourteen healthy men by exposing them to darkness and to light of 800 lux during a1-h period on two subsequent mornings. In the early morning, we demonstrated atemporary increase of salivary cortisol levels after awakening, while light exposureresulted in a +/- 35% further increase in cortisol levels. Cortisol levels 20 and 40min after waking were significantly higher during 800 lux exposure than duringdarkness. In order to investigate the time-dependency, the experiment wasrepeated in the late evening. In the evening, light had no effect on cortisol levels.These results demonstrate that light conditions in the early morning have a strongimpact on the morning-cortisol peak, but that evening cortisol levels are unaffectedby light. The possible role of the circadian pacemaker as mediator of the light effecton cortisol level is discussed.SchlagwörterAdult; Circadian Rhythm; Humans; Hydrocortisonemetabolism; Light; Male;Salivametabolism