Functional Morphology of the Suprachiasmatic Nucleus

Ibata, Yasuhiko; Okamura, Hitoshi; Tanaka, Masaki; Tamada, Yoshitaka; Hayashi, Seiji; Iijima, Norio; Matsuda, Tomoyuki; Munekawa, Katsuhiko; Takamatsu, Tetsuro; Hisa, Yasuo; Shigeyoshi, Yasufumi; Amaya, Fumimasa

doi:10.1006/frne.1999.0180

Cited by 73 publications

(42 citation statements)

References 99 publications

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“…The suprachiasmatic nucleus (SCN) is the primary generator of the circadian rhythm in mammals [reviewed by van den Pol and Dudek (1993); Ibata et al (1999); Hastings and Herzog, 2004]. Electrophysiological evidence from single-unit recordings (Green and Gillette, 1982) and days-long multiple-unit recordings of SCN neurons in hypothalamic slices (Bouskila and Dudek, 1993;Gribkoff et al, 2003) revealed that neurons in the isolated SCN generate a coordinated circadian rhythm of loosely synchronized electrical activity regulated by oscillatory mechanisms involving transcription and translation of circadian genes (Hastings and Herzog, 2004).…”

Section: Introductionmentioning

confidence: 99%

Connexin36 vs. connexin32, “miniature” neuronal gap junctions, and limited electrotonic coupling in rodent suprachiasmatic nucleus

et al. 2007

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Suprachiasmatic nucleus (SCN) neurons generate circadian rhythms, and these neurons normally exhibit loosely-synchronized action potentials. Although electrotonic coupling has long been proposed to mediate this neuronal synchrony, ultrastructural studies have failed to detect gap junctions between SCN neurons. Nevertheless, it has been proposed that neuronal gap junctions exist in the SCN; that they consist of connexin32 or, alternatively, connexin36; and that connexin36 knockout eliminates neuronal coupling between SCN neurons and disrupts circadian rhythms. We used confocal immunofluorescence microscopy and freeze-fracture replica immunogold labeling to examine the distributions of connexin30, connexin32, connexin36, and connexin43 in rat and mouse SCN and used whole-cell recordings to re-assess electrotonic and tracer coupling. Connexin32-immunofluorescent puncta were essentially absent in SCN but connexin36 was relatively abundant. Fifteen neuronal gap junctions were identified ultrastructurally, all of which contained connexin36 but not connexin32, whereas nearby oligodendrocyte gap junctions contained connexin32. In adult SCN, one neuronal gap junction was >600 connexons, whereas 75% were smaller than 50 connexons, which may be below the limit of detectability by fluorescence microscopy and thin-section electron microscopy. Whole-cell recordings in hypothalamic slices revealed tracer coupling with Neurobiotin in <5% of SCN neurons, and paired recordings (>40 pairs) did not reveal obvious electrotonic coupling or synchronized action potentials, consistent with few neurons possessing large gap junctions. However, most neurons had partial spikes or spikelets (often <1 mV), which remained after QX-314 had blocked sodium-mediated action potentials within the recorded neuron, consistent with spikelet transmission via small gap junctions. Thus, a few "miniature" gap junctions on most SCN neurons appear to mediate weak electrotonic coupling between limited numbers of neuron pairs, Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptNeuroscience. Author manuscript; available in PMC 2008 February 15. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript thus accounting for frequent detection of partial spikes and hypothetically providing the basis for "loose" electrical or metabolic synchronization of electrical activity commonly observed in SCN neuronal populations during circadian rhythms. Keywordsimmunocytochemistry; electrical synapse; freeze-fracture replica immunogold labeling; spikelet; metabolic coupling; syn...

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Section: Introductionmentioning

confidence: 99%

Connexin36 vs. connexin32, “miniature” neuronal gap junctions, and limited electrotonic coupling in rodent suprachiasmatic nucleus

et al. 2007

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“…The SCN is a heterogeneous nucleus with major subregional differences in neurochemical phenotype, connectivity and patterns of gene expression (3)(4)(5)(6). Light information is transmitted directly to the SCN via the retinohypothalamic tract (RHT) (7,8).…”

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Dissociation of circadian and light inhibition of melatonin release through forced desynchronization in the rat

Schwartz

Wotus

Liu

et al. 2009

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

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Pineal melatonin release exhibits a circadian rhythm with a tight nocturnal pattern. Melatonin synthesis is regulated by the master circadian clock within the hypothalamic suprachiasmatic nucleus (SCN) and is also directly inhibited by light. The SCN is necessary for both circadian regulation and light inhibition of melatonin synthesis and thus it has been difficult to isolate these two regulatory limbs to define the output pathways by which the SCN conveys circadian and light phase information to the pineal. A 22-h light-dark (LD) cycle forced desynchrony protocol leads to the stable dissociation of rhythmic clock gene expression within the ventrolateral SCN (vlSCN) and the dorsomedial SCN (dmSCN). In the present study, we have used this protocol to assess the pattern of melatonin release under forced desynchronization of these SCN subregions. In light of our reported patterns of clock gene expression in the forced desynchronized rat, we propose that the vlSCN oscillator entrains to the 22-h LD cycle whereas the dmSCN shows relative coordination to the light-entrained vlSCN, and that this dual-oscillator configuration accounts for the pattern of melatonin release. We present a simple mathematical model in which the relative coordination of a single oscillator within the dmSCN to a single light-entrained oscillator within the vlSCN faithfully portrays the circadian phase, duration and amplitude of melatonin release under forced desynchronization. Our results underscore the importance of the SCNs subregional organization to both photic input processing and rhythmic output control.circadian desynchronization ͉ dual oscillators ͉ suprachiasmatic I n mammals, circadian rhythms are governed by a master pacemaker located in the hypothalamic suprachiasmatic nucleus (SCN) (1, 2). The SCN is a heterogeneous nucleus with major subregional differences in neurochemical phenotype, connectivity and patterns of gene expression (3-6). Light information is transmitted directly to the SCN via the retinohypothalamic tract (RHT) (7,8). In rats, RHT input is dense in the ventrolateral SCN (vlSCN), and relatively sparse in the dorsomedial SCN (dmSCN) (3). In this species, segregation of SCN afferents is paralleled by a segregation of efferent projections emerging from each subregion, and some SCN targets receive input from only the vl-or the dmSCN (9). This topographic organization of afferent and efferent projections suggests different roles for these subregions regarding processing of photic information and control of circadian outputs. Indeed, photic stimulation by light pulses applied during the subjective night or by abruptly shifting the light-dark (LD) cycle up-regulates expression of the clock gene Per1 in the vlSCN, inducing a transient desynchronization in gene expression between the two subregions (10-13). These data strongly suggest that the SCNЈs subregional organization is key to the processing of light information. Its role in the control of circadian outputs, however, is more difficult to assess and has been limited t...

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“…In mammals, molecular oscillators exist in the suprachiasmatic nucleus (SCN) of the brain, a master clock (19,21,31), and also in peripheral tissues (24,48). Even in fibroblast cell lines, clock genes are induced rhythmically under certain conditions (1, 5, 47).…”

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confidence: 99%

Circadian and Light-Induced Transcription of Clock Gene Per1 Depends on Histone Acetylation and Deacetylation

Naruse

Oh‐hashi

Iijima

et al. 2004

Molecular and Cellular Biology

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Circadian clock genes are regulated through a transcriptional-translational feedback loop. Alterations of the chromatin structure by histone acetyltransferases and histone deacetylases (HDACs) are commonly implicated in the regulation of gene transcription. However, little is known about the transcriptional regulation of mammalian clock genes by chromatin modification. Here, we show that the state of acetylated histones fluctuated in parallel with the rhythm of mouse Per1 (mPer1) or mPer2 expression in fibroblast cells and liver. Mouse CRY1 (mCRY1) repressed transcription with HDACs and mSin3B, which was relieved by the HDAC inhibitor trichostatin A (TSA). In turn, TSA induced endogenous mPer1 expression as well as the acetylation of histones H3 and H4, which interacted with the mPer1 promoter region in fibroblast cells. Moreover, a light pulse stimulated rapid histone acetylation associated with the promoters of mPer1 or mPer2 in the suprachiasmatic nucleus (SCN) and the binding of phospho-CREB in the CRE of mPer1. We also showed that TSA administration into the lateral ventricle induced mPer1 and mPer2 expression in the SCN. Taken together, these data indicate that the rhythmic transcription and light induction of clock genes are regulated by histone acetylation and deacetylation.Most organisms have physiological and behavioral rhythms, so-called circadian rhythms, having an intrinsic period of approximately 24 h. The circadian clock is an endogenous oscillator that controls daily physiological and behavioral rhythms. In mammals, molecular oscillators exist in the suprachiasmatic nucleus (SCN) of the brain, a master clock (19,21,31), and also in peripheral tissues (24,48). Even in fibroblast cell lines, clock genes are induced rhythmically under certain conditions (1, 5, 47). The core circadian system consists of an interacting transcriptional-translational feedback loop of clock genes in an individual cell (11, 31). A negative feedback loop involves the regulation of two period genes (Per1 and -2) and two cryptochrome genes (Cry1 and -2) (22, 33). The rhythmic transcription is driven by the basic helix-loop-helix-PAS protein (CLOCK-BMAL1) complex, which binds the E-box on the mPer1 and mPer2 genes (14). This CLOCK-BMAL1-mediated transcription is, in turn, repressed by the translated products of clock genes, such as the mPER and mCRY protein complex, which translocate to the nucleus (14,17,22,33).On the other hand, rapid inductions of mPer1 and mPer2 are also involved in phase resetting of the circadian rhythm (3,4,34). A light pulse during subjective night induced rapid increases in mPer1 and mPer2 expression in the SCN and caused a behavioral phase shift. Thus, mPer1 and mPer2 are considered to work both in the generation of circadian rhythm and in light entrainment.It has recently become clear that histone modification plays an important role when genes are transcribed in the nucleus and basic domains in the histone N-terminal are modified, such as by phosphorylation, acetylation, methylation, or ubiquityla...

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Functional Morphology of the Suprachiasmatic Nucleus

Cited by 73 publications

References 99 publications

Connexin36 vs. connexin32, “miniature” neuronal gap junctions, and limited electrotonic coupling in rodent suprachiasmatic nucleus

Connexin36 vs. connexin32, “miniature” neuronal gap junctions, and limited electrotonic coupling in rodent suprachiasmatic nucleus

Dissociation of circadian and light inhibition of melatonin release through forced desynchronization in the rat

Circadian and Light-Induced Transcription of Clock Gene Per1 Depends on Histone Acetylation and Deacetylation

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