Regulation of Circadian Rhythmicity

Takahashi, Joseph S.; Zatz, Martin

doi:10.1126/science.6287576

Cited by 284 publications

(113 citation statements)

References 107 publications

(50 reference statements)

Supporting

Mentioning

110

Contrasting

Unclassified

Order By: Relevance

“…In the mouse central nervous system, NMU is expressed in the suprachiasmatic (SCN), dorsomedial (DMH), ventromedial (VMH) and arcuate nuclei of the hypothalamus (Graham et al 2003). These nuclei are important in controlling circadian rhythms, appetite and energy balance (Takahashi & Zatz 1982, Williams et al 2001. In contrast, NMU expression in the rat is limited to the SCN, relatively few diffuse cells in the arcuate nuclei and DMH in the hypothalamus and the nuclei of the solitary tract (NTS) and the inferior olive in the brainstem (Ivanov et al 2002, Graham et al 2003.…”

Section: Introductionmentioning

confidence: 99%

Negative energy balance and leptin regulate neuromedin-U expression in the rat pars tuberalis

Nogueiras¹,

Tovar²,

Mitchell³

et al. 2006

Journal of Endocrinology

View full text Add to dashboard Cite

Central neuromedin U (NMU) functions in energy balance, the hypothalamic-pituitary-adrenal axis, LH release and circadian rhythmicity. In rats, high levels of NMU occur in the hypothalamic suprachiasmatic nuclei and the pars tuberalis of the pituitary. NMU expression in the pars tuberalis appears to be downregulated in the Zucker fatty (fa/fa) rat, lacking functional leptin receptors. In contrast, in the dorsomedial (DMH) nuclei of the mouse, NMU expression is higher in the ob/ob mouse, lacking leptin, and is upregulated by fasting. However, leptin appears not to change NMU gene expression in either the mouse DMH or the rat pars tuberalis. Thus, the present study aims to better identify factors influencing central NMU expression in the rat pars tuberalis. SpragueDawley rats were fasted and/or challenged with intracerebroventricular leptin or ghrelin and gene expression was measured using real-time reverse transcriptase-PCR and quantitative in situ hybridisation with riboprobes specific for NMU and NMU receptor (NMU-R2). NMU expression in the rat pars tuberalis was elevated by fasting. Ghrelin administration had no effect on the level of NMU expression, but leptin was found to diminish the expression in a concentration-and time-dependent manner. NMU-R2 expression was unchanged in any of the groups measured. These results suggest that NMU expression in rat pars tuberalis is upregulated in states of negative energy balance, and this may be mediated indirectly by changes in leptin levels. These results demonstrate a link between energy balance and NMU expression in the pars tuberalis of the pituitary.

show abstract

Section: Introductionmentioning

confidence: 99%

Negative energy balance and leptin regulate neuromedin-U expression in the rat pars tuberalis

Nogueiras¹,

Tovar²,

Mitchell³

et al. 2006

Journal of Endocrinology

View full text Add to dashboard Cite

show abstract

“…Increasing evidence suggests that the suprachiasmatic nucleus (SCN) of the hypothalamus is the major pacemaker for circadian rhythms in mammals (Rusak & Zucker, 1979;Takahashi & Zatz, 1982;Turek, 1985;Meijer & Rietveld, 1989). Bilateral lesion of the SCN eliminates endogenous behavioural and hormonal rhythms (Moore & Eichler, 1972;Stephan & Zucker, 1972;Reppert, Perlow, Ungerleider, Mishkin, Tamarkin, Orloff, Hoffman & Klein, 1981), whereas transplantation of neural tissue containing SCN neurons to the third ventricle of the SONlesioned arrhythmic host restores disrupted circadian rhythms (Ralph, Foster, Davis & Menaker, 1990).…”

Section: Introductionmentioning

confidence: 99%

Intracellular electrophysiological study of suprachiasmatic nucleus neurons in rodents: excitatory synaptic mechanisms.

Kim¹,

Dudek²

1991

The Journal of Physiology

134

View full text Add to dashboard Cite

SIUMMARY1. To study the synaptic mechanisms of excitatory transmission in the suprachiasmatic nucleus (SCN), we assessed the effects of excitatory amino acid receptor antagonists on excitatory postsynaptic potentials (EPSPs) recorded from SCN neurons in horizontal and parasagittal hypothalamic slice preparations from rats and guinea-pigs. The EPSPs were evoked by electrical stimulation of either optic nerve or a site near the SCN.2. When evoked at membrane potentials between -60 and -100 mV, the EPSPs from optic nerve stimulation were conventional in shape; they rose to the peak quickly (6'2 + 0-5 ms, mean + s.E.M.; n = 45) and decayed gradually over 50-250 ms. When evoked at membrane potentials between -20 and -55 mV after blockade of outward K+ currents and fast Na+ spikes by intracellular injection of Cs+ and QX-314 (n = 5 neurons), a slow depolarizing potential emerged near the fast peak of the EPSP. This slow potential, unlike the fast peak, was not linearly related to membrane potential.3. An antagonist for kainate-and quisqualate-type excitatory amino acid receptors, 6,7-dinitroquinoxaline-2,3-dione (DNQX 1-10 gM), depressed in a concentration-dependent and reversible manner the EPSPs evoked by optic nerve stimulation at membrane potentials between -60 and -100 mV (n = 9). The effects of DNQX were not associated with any significant changes in the baseline input resistance or membrane potential of the postsynaptic neurons. The selective Nmethyl-D-aspartate (NMDA) receptor antagonist, DL-2-amino-5-phosphonopentanoic acid (AP5, 50-100 ,UM), did not affect significantly and donsistently the EPSPs evoked at these membrane potentials (n = 7). On the other hand, AP5 (50 uM) blocked or depressed the slow depolarizing component of the EPSPs evoked at membrane potentials between -20 and -55 mV (n = 4). No significant changes in baseline input resistance or membrane potential accompanied the effects of AP5. 4. Stimulation of a site lateral or dorsocaudal to the SCN evoked EPSPs distinct from those evoked by optic nerve stimulation. Again, DNQX (0-3-10 gM) depressed the EPSPs evoked at membrane potentials between -60 and -100mV (n =4) whereas AP5 (50gM) had no effect (n = 5). When evoked at less negative membrane potentials (i.e. -20 to -55 mV) after intracellular injection of Cs+ and QX-314, the MS 9115 Y I. KIM AND F. E DUDEK EPSPs had a slow depolarizing potential, similar to the EPSPs from optic nerve stimulation. The slow potential, which often triggered a presumed high-threshold Ca2+ spike, was blocked or depressed significantly by AP5 (50 gM, n = 3).5. The present results suggest that, at resting or more negative membrane potentials, non-NMDA receptors mediate excitatory synaptic transmission for both retinal and non-retinal inputs to SCN neurons; at less negative potentials, however, NMDA receptors may also play a role in excitatory synaptic transmission.

show abstract

“…On the other hand, circadian amplitude, a measure of robustness, is technically more difficult to quantify and can be influenced by a number of downstream factors (30,31). Circadian reporter assays based upon the cycling core clock elements are ideal for screens because they are close to the mechanism, can be measured in real time, and can be used to estimate rhythm amplitude.…”

mentioning

confidence: 99%

Identification of diverse modulators of central and peripheral circadian clocks by high-throughput chemical screening

Chen

Yoo

Park

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

175

196

View full text Add to dashboard Cite

The circadian clock coordinates daily oscillations of essential physiological and behavioral processes. Conversely, aberrant clocks with damped amplitude and/or abnormal period have been associated with chronic diseases and aging. To search for small molecules that perturb or enhance circadian rhythms, we conducted a high-throughput screen of approximately 200,000 synthetic compounds using Per2∷lucSV reporter fibroblast cells and validated 11 independent classes of molecules with Bmal1:luciferase reporter cells as well as with suprachiasmatic nucleus and peripheral tissue explants. Four compounds were found to lengthen the period in both central and peripheral clocks, including three compounds that inhibited casein kinase I ε in vitro and a unique benzodiazepine derivative acting through a non-GABA A receptor target. In addition, two compounds acutely induced Per2∷lucSV reporter bioluminescence, delayed the rhythm, and increased intracellular cAMP levels, but caused rhythm damping. Importantly, five compounds shortened the period of peripheral clocks; among them, four compounds also enhanced the amplitude of central and/or peripheral reporter rhythms. Taken together, these studies highlight diverse activities of drug-like small molecules in manipulating the central and peripheral clocks. These small molecules constitute a toolbox for probing clock regulatory mechanisms and may provide putative lead compounds for treatment of clock-associated diseases.

show abstract

Regulation of Circadian Rhythmicity

Cited by 284 publications

References 107 publications

Negative energy balance and leptin regulate neuromedin-U expression in the rat pars tuberalis

Negative energy balance and leptin regulate neuromedin-U expression in the rat pars tuberalis

Intracellular electrophysiological study of suprachiasmatic nucleus neurons in rodents: excitatory synaptic mechanisms.

Identification of diverse modulators of central and peripheral circadian clocks by high-throughput chemical screening

Contact Info

Product

Resources

About