A riot of rhythms: neuronal and glial circadian oscillators in the mediobasal hypothalamus

Guilding, Clare; Hughes, Alun; Brown, T. M.; Namvar, Sara; Piggins, Hugh D.

doi:10.1186/1756-6606-2-28

Cited by 154 publications

(207 citation statements)

References 71 publications

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“…These findings are supported by work showing, respectively, that the Arc contains molecular clocks (1) that are reset in response to restricted meals (54) or fasting (32) and by the well-established finding that the SCN contains clocks that respond to photic cues. These results, therefore, add to the Arc's many roles an underappreciated functional circadian relationship with the SCN (60,68,78), as well as revealing an essential role for the Arc in maintaining circadian rhythms of ad libitum feeding independent of light entrainment.…”

Section: Discussionsupporting

confidence: 72%

“…Neurons exhibiting robust circadian rhythms that would be potentially capable of controlling circadian feeding rhythms are present in the Arc (1,32,37,54,81). Not only do Arc leptin receptors exhibit diurnal variation (25), but Arc LepR-B-expressing neurons receive and appear to integrate food-and energyrelated signals arising from diverse central and peripheral sites (9,17,45,88,95).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, the Arc contains oscillators that maintain their intrinsic rhythms for several days in culture (1). The rhythms of some Arc oscillators are shifted in response to the anticipation of a restricted meal (54) or to fasting (32). Some are entrained to the photoperiod but, unlike those in the suprachiasmatic nucleus (SCN), exhibit peaks during the night (1).…”

mentioning

confidence: 99%

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Leptin-sensitive neurons in the arcuate nuclei contribute to endogenous feeding rhythms

Wiater

Oostrom

et al. 2012

American Journal of Physiology-Regulatory, Integrative and Comp

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Li AJ, Wiater MF, Oostrom MT, Smith BR, Wang Q, Dinh TT, Roberts BL, Jansen HT, Ritter S. Leptin-sensitive neurons in the arcuate nuclei contribute to endogenous feeding rhythms. Am J Physiol Regul Integr Comp Physiol 302: R1313-R1326, 2012. First published April 4, 2012 doi:10.1152/ajpregu.00086.2012.-Neural sites that interact with the suprachiasmatic nuclei (SCN) to generate rhythms of unrestricted feeding remain unknown. We used the targeted toxin, leptin conjugated to saporin (Lep-SAP), to examine the importance of leptin receptor-B (LepR-B)-expressing neurons in the arcuate nucleus (Arc) for generation of circadian feeding rhythms. Rats given Arc Lep-SAP injections were initially hyperphagic and rapidly became obese (the "dynamic phase" of weight gain). During this phase, Lep-SAP rats were arrhythmic under 12:12-h light-dark (LD) conditions, consuming 59% of their total daily intake during the daytime, compared with 36% in blank-SAP (B-SAP) controls. Lep-SAP rats were also arrhythmic in continuous dark (DD), while significant circadian feeding rhythms were detected in all B-SAP controls. Approximately 8 wk after injection, Lep-SAP rats remained obese but transitioned into a "static phase" of weight gain marked by attenuation of their hyperphagia and rate of weight gain. In this phase, Arc Lep-SAP rats exhibited circadian feeding rhythms under LD conditions, but were arrhythmic in continuous light (LL) and DD. Lep-SAP injections into the ventromedial hypothalamic nucleus did not cause hyperphagia, obesity, or arrhythmic feeding in either LD or DD. Electrolytic lesion of the SCN produced feeding arrhythmia in DD but not hyperphagia or obesity. Results suggest that both Arc Lep-SAP neurons and SCN are required for generation of feeding rhythms entrained to photic cues, while also revealing an essential role for the Arc in maintaining circadian rhythms of ad libitum feeding independent of light entrainment.

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Section: Discussionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Leptin-sensitive neurons in the arcuate nuclei contribute to endogenous feeding rhythms

Wiater

Oostrom

et al. 2012

American Journal of Physiology-Regulatory, Integrative and Comp

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“…However, a large body of work has revealed that the mediobasal hypothalamic area (MBH), defined here as including the arcuate (Arc) and ventromedial nuclei, is a critical site for detection and integration of signals governing metabolism and feeding (6,27,29,75). Circadian oscillators capable of sustaining their rhythms ex vivo for up to 3 days have been demonstrated in the MBH (1,21). In some of these, the phase of the oscillation was altered by restricted feeding (21).…”

mentioning

confidence: 99%

Circadian integration of sleep-wake and feeding requires NPY receptor-expressing neurons in the mediobasal hypothalamus

Wiater

Mukherjee

et al. 2011

American Journal of Physiology-Regulatory, Integrative and Comp

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Sleep and feeding rhythms are highly coordinated across the circadian cycle, but the brain sites responsible for this coordination are unknown. We examined the role of neuropeptide Y (NPY) receptor-expressing neurons in the mediobasal hypothalamus (MBH) in this process by injecting the targeted toxin, NPY-saporin (NPY-SAP), into the arcuate nucleus (Arc). NPY-SAP-lesioned rats were initially hyperphagic, became obese, exhibited sustained disruption of circadian feeding patterns, and had abnormal circadian distribution of sleep-wake patterns. Total amounts of rapid eye movement sleep (REMS) and non-REMS (NREMS) were not altered by NPY-SAP lesions, but a peak amount of REMS was permanently displaced to the dark period, and circadian variation in NREMS was eliminated. The phase reversal of REMS to the dark period by the lesion suggests that REMS timing is independently linked to the function of MBH NPY receptor-expressing neurons and is not dependent on NREMS pattern, which was altered but not phase reversed by the lesion. Sleep-wake patterns were altered in controls by restricting feeding to the light period, but were not altered in NPY-SAP rats by restricting feeding to either the light or dark period, indicating that disturbed sleep-wake patterns in lesioned rats were not secondary to changes in food intake. Sleep abnormalities persisted even after hyperphagia abated during the static phase of the lesion. Results suggest that the MBH is required for the essential task of integrating sleep-wake and feeding rhythms, a function that allows animals to accommodate changeable patterns of food availability. NPY receptor-expressing neurons are key components of this integrative function. arcuate nucleus; NPY-saporin; obesity; rapid eye movement sleep FEEDING AND VIGILANCE (sleep-wake) states are rhythmically expressed across the circadian cycle, and their rhythms are highly integrated (3,64,75). Integration of sleep-wake and feeding rhythms is of fundamental importance for survival. Indeed, a wakeful state is an intrinsic requirement for feeding and foraging behavior, and, in a changeable environment, only close communication between these particular rhythms would permit an animal to respond adaptively and opportunistically to changing patterns of food availability. Although the suprachiasmatic nucleus of the hypothalamus (SCN) has an acknowledged role in establishing and maintaining circadian rhythms (47,63,83), including sleep-wake rhythms (15), entrainment of circadian food-anticipatory rhythms does not require the SCN (79,82), supporting the possibility that integration of sleep-wake and feeding also occurs outside the SCN. Furthermore, integration of physiological signals required to derive rhythms compatible with homeostatic requirements is likely to occur outside the SCN (6,48,75), as this arrangement would provide maximum flexibility for responding to varying challenges.Surprisingly few experiments have attempted to determine sites responsible for integration of sleep and feeding rhythms. However, a large body o...

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“…Many recent studies have taken advantage of the mPER2::LUC fusion knock-in reporter mouse 4,5,9,19,25,[29][30][31]43 . This reporter system allows circadian phenotyping of cells and tissue explants including the SCN.…”

Section: Luciferase Reportersmentioning

confidence: 99%

Monitoring Cell-autonomous Circadian Clock Rhythms of Gene Expression Using Luciferase Bioluminescence Reporters

Ramanathan

Khan

Kathale

et al. 2012

JoVE

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In mammals, many aspects of behavior and physiology such as sleep-wake cycles and liver metabolism are regulated by endogenous circadian clocks (reviewed 1,2 ). The circadian time-keeping system is a hierarchical multi-oscillator network, with the central clock located in the suprachiasmatic nucleus (SCN) synchronizing and coordinating extra-SCN and peripheral clocks elsewhere 1,2 . Individual cells are the functional units for generation and maintenance of circadian rhythms 3,4 , and these oscillators of different tissue types in the organism share a remarkably similar biochemical negative feedback mechanism. However, due to interactions at the neuronal network level in the SCN and through rhythmic, systemic cues at the organismal level, circadian rhythms at the organismal level are not necessarily cell-autonomous [5][6][7] . Compared to traditional studies of locomotor activity in vivo and SCN explants ex vivo, cell-based in vitro assays allow for discovery of cell-autonomous circadian defects 5,8 . Strategically, cell-based models are more experimentally tractable for phenotypic characterization and rapid discovery of basic clock mechanisms 5,[8][9][10][11][12][13] . Because circadian rhythms are dynamic, longitudinal measurements with high temporal resolution are needed to assess clock function. In recent years, real-time bioluminescence recording using firefly luciferase as a reporter has become a common technique for studying circadian rhythms in mammals 14,15 , as it allows for examination of the persistence and dynamics of molecular rhythms. To monitor cell-autonomous circadian rhythms of gene expression, luciferase reporters can be introduced into cells via transient transfection 13,16,17 or stable transduction 5,10,18,19 . Here we describe a stable transduction protocol using lentivirus-mediated gene delivery. The lentiviral vector system is superior to traditional methods such as transient transfection and germline transmission because of its efficiency and versatility: it permits efficient delivery and stable integration into the host genome of both dividing and non-dividing cells 20 . Once a reporter cell line is established, the dynamics of clock function can be examined through bioluminescence recording. We first describe the generation of P(Per2)-dLuc reporter lines, and then present data from this and other circadian reporters. In these assays, 3T3 mouse fibroblasts and U2OS human osteosarcoma cells are used as cellular models. We also discuss various ways of using these clock models in circadian studies. Methods described here can be applied to a great variety of cell types to study the cellular and molecular basis of circadian clocks, and may prove useful in tackling problems in other biological systems. Video LinkThe video component of this article can be found at http://www.jove.com/video/4234/ Protocol Construction of Lentiviral Luciferase ReportersA mammalian circadian reporter construct usually contains an expression cassette in which a circadian promoter is fused with the lucifer...

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A riot of rhythms: neuronal and glial circadian oscillators in the mediobasal hypothalamus

Cited by 154 publications

References 71 publications

Leptin-sensitive neurons in the arcuate nuclei contribute to endogenous feeding rhythms

Leptin-sensitive neurons in the arcuate nuclei contribute to endogenous feeding rhythms

Circadian integration of sleep-wake and feeding requires NPY receptor-expressing neurons in the mediobasal hypothalamus

Monitoring Cell-autonomous Circadian Clock Rhythms of Gene Expression Using Luciferase Bioluminescence Reporters

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