Specializations of gastrin‐releasing peptide cells of the mouse suprachiasmatic nucleus

Drouyer, Elise; LeSauter, Joseph; Hernandez, Amanda; Silver, Rae

doi:10.1002/cne.22272

Cited by 29 publications

(33 citation statements)

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“…Their surgical separation desynchronizes the dorsomedial shell, presumably due to loss of VIPand GRP-ergic signals (29), and a simple model is that core and shell contain reciprocally supportive oscillators coupled by peptidergic signals. Thus, the shell receives a dense innervation by VIP and GRP (30) and expresses VPAC2 (31) and BB2r (26) whereas the V1a receptor is widely distributed across SCN (27). This model complements the conclusion that there is no uniquely specialized or anatomically localized class of cell-autonomous pacemakers (11): rather, AVP, VIP, and other SCN neurons are intrinsic but unstable circadian oscillators that rely on network interactions to stabilize their otherwise noisy cycling.…”

Section: Discussionmentioning

confidence: 76%

A diversity of paracrine signals sustains molecular circadian cycling in suprachiasmatic nucleus circuits

Maywood

Chesham²,

O’Brien³

et al. 2011

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

260

311

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The suprachiasmatic nucleus (SCN) is the principal circadian pacemaker of mammals, coordinating daily rhythms of behavior and metabolism. Circadian timekeeping in SCN neurons revolves around transcriptional/posttranslational feedback loops, in which Period (Per) and Cryptochrome (Cry) genes are negatively regulated by their protein products. Recent studies have revealed, however, that these "core loops" also rely upon cytosolic and circuit-level properties for sustained oscillation. To characterize interneuronal signals responsible for robust pacemaking in SCN cells and circuits, we have developed a unique coculture technique using wild-type (WT) "graft" SCN to drive pacemaking (reported by PER2::LUCIFER-ASE bioluminescence) in "host" SCN deficient either in elements of neuropeptidergic signaling or in elements of the core feedback loop. We demonstrate that paracrine signaling is sufficient to restore cellular synchrony and amplitude of pacemaking in SCN circuits lacking vasoactive intestinal peptide (VIP). By using grafts with mutant circadian periods we show that pacemaking in the host SCN is specified by the genotype of the graft, confirming graft-derived factors as determinants of the host rhythm. By combining pharmacological with genetic manipulations, we show that a hierarchy of neuropeptidergic signals underpins this paracrine regulation, with a preeminent role for VIP augmented by contributions from arginine vasopressin (AVP) and gastrin-releasing peptide (GRP). Finally, we show that interneuronal signaling is sufficiently powerful to maintain circadian pacemaking in arrhythmic Cry-null SCN, deficient in essential elements of the transcriptional negative feedback loops. Thus, a hierarchy of paracrine neuropeptidergic signals determines cell-and circuit-level circadian pacemaking in the SCN.T he circadian pacemaker of the suprachiasmatic nucleus (SCN) directs, on a daily basis, the most fundamental processes of physiology and metabolism, sleep and wakefulness (1). The established molecular model of the SCN oscillator involves interlocked transcriptional/posttranslational negative feedback loops, centered on rhythmic expression of the transcriptional inhibitors Period (Per) and Cryptochrome (Cry), driven by the positive activators Clock and Bmal1. The period of the daily oscillation is determined by the transcriptional activity of Clock (1) and by the stability of Per and Cry proteins (2, 3). More recently the model of SCN neurons as autonomous transcriptional/translational feedback oscillators has been reappraised. Rhythmic cytosolic signaling pathways, particularly cAMP and Ca 2+ , not only are driven by the core feedback loops, but also support them in a mutually dependent fashion (4, 5). Furthermore, within SCN circuits, loss of signaling by the neuropeptide vasoactive intestinal peptide (VIP) through its VPAC2 receptor (a positive regulator of cAMP) both desynchronizes and damps cellular transcriptional pacemaking (6, 7). Conversely, intercellular coupling maintains robustness within SCN cells deficie...

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Section: Discussionmentioning

confidence: 76%

A diversity of paracrine signals sustains molecular circadian cycling in suprachiasmatic nucleus circuits

Maywood

Chesham²,

O’Brien³

et al. 2011

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

260

311

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“…In contrast, calbindin-expressing SCN neurons fire action potentials in a rhythmic manner (Jobst and Allen 2002). Similarly, gastrin-releasing peptide (GRP)-expressing neurons do not show a circadian pattern of clock gene expression, suggesting they may not fire action potentials in a circadian pattern (Drouyer et al 2010). The circadian output is the combination of rhythmically and nonrhythmically firing neurons present in individual compartments of the SCN.…”

Section: Scn Neuronal Heterogeneitymentioning

confidence: 99%

Membrane Currents, Gene Expression, and Circadian Clocks

Allen

Nitabach

Colwell

2017

Cold Spring Harb Perspect Biol

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Neuronal circadian oscillators in the mammalian and Drosophila brain express a circadian clock comprised of interlocking gene transcription feedback loops. The genetic clock regulates the membrane electrical activity by poorly understood signaling pathways to generate a circadian pattern of action potential firing. During the day, Na þ channels contribute an excitatory drive for the spontaneous activity of circadian clock neurons. Multiple types of K þ channels regulate the action potential firing pattern and the nightly reduction in neuronal activity. The membrane electrical activity possibly signaling by changes in intracellular Ca 2þ and cyclic adenosine monophosphate (cAMP) regulates the activity of the gene clock. A decline in the signaling pathways that link the gene clock and neural activity during aging and disease may weaken the circadian output and generate significant impacts on human health. N eurons in the suprachiasmatic nucleus (SCN) function as part of a central timing circuit that drives daily changes in our behavior and underlying physiology. A hallmark feature of SCN neurons is that they are electrically silent during the night, start firing action potentials near dawn, and then continue to generate action potentials with a slow and steady pace all day long. These rhythms in electrical activity are critical for the function of the circadian timing system. This article reviews what is known about the ionic and molecular mechanisms driving the rhythmic firing patterns in our body's clock. We raise the hypothesis that a decline in neural activity in the central clock may be a critical mechanism by which aging and disease may weaken the circadian output and contribute to a set of symptoms that impacts human health. THE IONIC MECHANISMS UNDERLYING NEURAL ACTIVITY RHYTHMSSCN neurons generate action potentials in the absence of synaptic drive, and can therefore be considered endogenously active neurons.

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“…Breeding parents were homozygote transgenic mice bearing a jellyfish GFP reporter (calbindin-D28K-BAC::GFP transgenic mouse; a generous gift of Dr. N. Heintz, Rockefeller University, New York, NY). We have previously shown that 87% of GFPϩ neurons contain calbindin in 7-day-old pups (Drouyer et al 2010) and 90% of GFPϩ cells contain GRP in the adult (Karatsoreos et al 2004). Here, we have assumed, based on the uniformity of the data set, that all GFPimmunoreactive neurons contain GRP.…”

Section: Animalsmentioning

confidence: 99%

“…They make appositions onto other GRPϩ cells and exhibit dye coupling, suggestive of gap junctions. Dendrites and axons of GRPϩ cells make appositions onto arginine vasopressin (AVP) neurons, whereas the adjacent non-GRP cells have a less extensive fiber network, largely confined to the region of GRPϩ cells (Drouyer et al 2010).…”

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confidence: 99%

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Light exposure induces short- and long-term changes in the excitability of retinorecipient neurons in suprachiasmatic nucleus

LeSauter

Silver

Cloues

et al. 2011

Journal of Neurophysiology

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LeSauter J, Silver R, Cloues R, Witkovsky P. Light exposure induces short-and long-term changes in the excitability of retinorecipient neurons in suprachiasmatic nucleus. J Neurophysiol 106: 576 -588, 2011. First published May 18, 2011 doi:10.1152/jn.00060.2011.-The suprachiasmatic nucleus (SCN) is the locus of a hypothalamic circadian clock that synchronizes physiological and behavioral responses to the daily light-dark cycle. The nucleus is composed of functionally and peptidergically diverse populations of cells for which distinct electrochemical properties are largely unstudied. SCN neurons containing gastrin-releasing peptide (GRP) receive direct retinal input via the retinohypothalamic tract. We targeted GRP neurons with a green fluorescent protein (GFP) marker for whole cell patch-clamping. In these neurons, we studied short (0.5-1.5 h)-and long-term (2-6 h) effects of a 1-h light pulse (LP) given 2 h after lights off [Zeitgeber time (ZT) 14:00 -15:00] on membrane potential and spike firing. In brain slices taken from light-exposed animals, cells were depolarized, and spike firing rate increased between ZT 15:30 and 16:30. During a subsequent 4-h period beginning around ZT 17:00, GRP neurons from light-exposed animals were hyperpolarized by ϳ15 mV. None of these effects was observed in GRP neurons from animals not exposed to light or in immediately adjacent non-GRP neurons whether or not exposed to light. Depolarization of GRP neurons was associated with a reduction in GABA A -dependent synaptic noise, whereas hyperpolarization was accompanied both by a loss of GABA A drive and suppression of a TTX-resistant leakage current carried primarily by Na. This suggests that, in the SCN, exposure to light may induce a short-term increase in GRP neuron excitability mediated by retinal neurotransmitters and neuropeptides, followed by long-term membrane hyperpolarization resulting from suppression of a leakage current, possibly resulting from genomic signals.gastrin-releasing peptide; sustained inward current; GABA A receptor; patch-clamp THE SUPRACHIASMATIC NUCLEUS (SCN) of the mammalian hypothalamus is the locus of the principal circadian pacemaker in the body, which serves to coordinate rhythmicity in many physiological and behavioral responses (Klein et al. 1991). Light is the most salient external cue synchronizing the freerunning endogenous oscillation of the SCN to the day-night cycle of the local environment (Meijer and Schwartz 2003), but the mechanisms by which light modulates the excitability and rhythmicity of SCN neurons are not fully understood. One difficulty is that the SCN is functionally, anatomically, and peptidergically heterogeneous (Silver and Schwartz 2005). Directly retinorecipient neurons, concentrated in a ventrolateral core region, transmit signals to the SCN shell region (Leak et al. 1999); for terminological clarification, see Morin and Allen (2006). Extracellular single-unit recordings, performed primarily in rat and hamster, show that ϳ33% of SCN neurons are light-responsive and exhib...

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Specializations of gastrin‐releasing peptide cells of the mouse suprachiasmatic nucleus

Cited by 29 publications

References 55 publications

A diversity of paracrine signals sustains molecular circadian cycling in suprachiasmatic nucleus circuits

A diversity of paracrine signals sustains molecular circadian cycling in suprachiasmatic nucleus circuits

Membrane Currents, Gene Expression, and Circadian Clocks

Light exposure induces short- and long-term changes in the excitability of retinorecipient neurons in suprachiasmatic nucleus

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