Disrupted Neuronal Activity Rhythms in the Suprachiasmatic Nuclei of Vasoactive Intestinal Polypeptide-Deficient Mice

Faculty of Life Sciences, University of Manchester, Manchester, UK M139PT.
Journal of Neurophysiology (Impact Factor: 2.89). 04/2007; 97(3):2553-8. DOI: 10.1152/jn.01206.2006
Source: PubMed


Vasoactive intestinal polypeptide (VIP), acting via the VPAC(2) receptor, is a key signaling pathway in the suprachiasmatic nuclei (SCN), the master clock controlling daily rhythms in mammals. Most mice lacking functional VPAC(2) receptors are unable to sustain behavioral rhythms and lack detectable SCN electrical rhythms in vitro. Adult mice that do not produce VIP (VIP/PHI(-/-)) exhibit less severe alterations in wheel-running rhythms, but the effects of this deficiency on the amplitude, phasing, or periodicity of their SCN cellular rhythms are unknown. To investigate this, we used suction electrodes to extracellularly record multiple- and single-unit electrical activity in SCN brain slices from mice with varying degrees of VIP deficiency, ranging from wild-type (VIP/PHI(+/+)) to heterozygous (VIP/PHI(+/-)) and VIP/PHI(-/-) animals. We found decreasing proportions of rhythmic cells in SCN slices from VIP/PHI(+/+) ( approximately 91%, n = 23) through VIP/PHI(-/+) ( approximately 71%, n = 28) to VIP/PHI(-/-) mice (62%; n = 37) and a parallel trend toward decreasing amplitude in the remaining rhythmic cells. SCN neurons from VIP/PHI(-/-) mice exhibited a broad range in the period and phasing of electrical rhythms, concordant with the known alterations in their behavioral rhythms. Further, treatment of VIP/PHI(-/-) slices with a VPAC(2) receptor antagonist significantly reduced the proportion of oscillating neurons, suggesting that VPAC(2) receptors still become activated in the SCN of these mice. The results establish that VIP is important for appropriate periodicity and phasing of SCN neuronal rhythms and suggest that residual VPAC(2) receptor signaling promotes rhythmicity in adult VIP/PHI(-/-) mice.

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Available from: Christopher S Colwell, Apr 14, 2014
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    • "Mice lacking vasoactive intestinal peptide (VIP) or its cognate receptor, VIP receptor 2 (VPAC2), are behaviorally arrhythmic, and cellular transcriptional cycles in the SCN are desynchronised and of low amplitude and coherence (Harmar et al., 2002; Colwell et al., 2003). The effects of a VPAC2 antagonist are even greater than those seen in VPAC2-null animals, suggesting that other ligands at this receptor may partially substitute for VIP (Brown et al., 2007). Consistent with this observation, transcriptional cycles in the VIP-null and VPAC2-null SCN can be restored by paracrine cues, including gastrin-releasing peptide and arginine vasopressin (Harmar et al., 2002; Hastings et al., 2008; Maywood et al., 2011). "
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    ABSTRACT: To serve as a robust internal circadian clock, the cell-autonomous molecular and electrophysiological activities of the individual neurons of the mammalian suprachiasmatic nucleus (SCN) are coordinated in time and neuroanatomical space. Although the contributions of the chemical and electrical interconnections between neurons are essential to this circuit-level orchestration, the features upon which they operate to confer robustness to the ensemble signal are not known. To address this, we applied several methods to deconstruct the interactions between the spatial and temporal organisation of circadian oscillations in organotypic slices from mice with circadian abnormalities. We studied the SCN of mice lacking Cryptochrome genes (Cry1 and Cry2), which are essential for cell-autonomous oscillation, and the SCN of mice lacking the vasoactive intestinal peptide receptor 2 (VPAC2-null), which is necessary for circuit-level integration, in order to map biological mechanisms to the revealed oscillatory features. The SCN of wild-type mice showed a strong link between the temporal rhythm of the bioluminescence profiles of PER2::LUC and regularly repeated spatially organised oscillation. The Cry-null SCN had stable spatial organisation but lacked temporal organisation, whereas in VPAC2-null SCN some specimens exhibited temporal organisation in the absence of spatial organisation. The results indicated that spatial and temporal organisation were separable, that they may have different mechanistic origins (cell-autonomous vs. interneuronal signaling) and that both were necessary to maintain robust and organised circadian rhythms throughout the SCN. This study therefore provided evidence that the coherent emergent properties of the neuronal circuitry, revealed in the spatially organised clusters, were essential to the pacemaking function of the SCN.
    European Journal of Neuroscience 06/2014; 40(3). DOI:10.1111/ejn.12631 · 3.18 Impact Factor
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    • "Furthermore, our ISH time course showed that clock and clock-controlled gene expression is still temporally regulated in vivo after Lhx1 deletion (Figures 3D–3F and S3A–S3C). These deficits are similar to what has been observed shortly after culturing Vipr2 À/À SCN slices (Brown et al., 2007). "
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    ABSTRACT: Vertebrate circadian rhythms are organized by the hypothalamic suprachiasmatic nucleus (SCN). Despite its physiological importance, SCN development is poorly understood. Here, we show that Lim homeodomain transcription factor 1 (Lhx1) is essential for terminal differentiation and function of the SCN. Deletion of Lhx1 in the developing SCN results in loss of SCN-enriched neuropeptides involved in synchronization and coupling to downstream oscillators, among other aspects of circadian function. Intact, albeit damped, clock gene expression rhythms persist in Lhx1-deficient SCN; however, circadian activity rhythms are highly disorganized and susceptible to surprising changes in period, phase, and consolidation following neuropeptide infusion. Our results identify a factor required for SCN terminal differentiation. In addition, our in vivo study of combinatorial SCN neuropeptide disruption uncovered synergies among SCN-enriched neuropeptides in regulating normal circadian function. These animals provide a platform for studying the central oscillator's role in physiology and cognition.
    Cell Reports 04/2014; 7(3). DOI:10.1016/j.celrep.2014.03.060 · 8.36 Impact Factor
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    • "Application of VIP alters the firing rate of SCN neurons (Reed et al., 2002), induces Per1 expression (Nielsen et al., 2002), and causes phase shifts of the SCN circadian rhythm (Reed et al., 2001; Meyer-Spasche & Piggins, 2004; An et al., 2011). The loss of VIP or its receptor [VIP receptor 2 (VIPR2)] disrupts neural activity rhythms of the SCN measured in vitro (Cutler et al., 2003; Brown et al., 2007), at least partly because of loss of synchrony of the SCN cell population (Aton et al., 2005; Ciarleglio et al., 2009). Behaviorally, all VIP-deficient and VIP2R-deficient mice exhibit disruptions in their ability to express a coherent circadian rhythm in constant darkness (DD) as well as alterations in their ability to synchronize to the LD cycle (Harmar et al., 2002; Colwell et al., 2003; Aton et al., 2005; Ciarleglio et al., 2009). "
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    ABSTRACT: The neuropeptide vasoactive intestinal peptide (VIP) is critical for the proper functioning of the neural circuit that generates circadian rhythms. Mice lacking VIP show profound deficits in the ability to generate many behavioral and physiological rhythms. To explore how the loss of VIP impacts on the intact circadian system, we carried out in vivo multiunit neural activity (MUA) recordings from the suprachiasmatic nucleus of freely moving VIP knockout (KO) mice. The MUA rhythms were largely unaltered in the VIP KO mice, with no significant differences being seen in the amplitude or phase of the rhythms in light-dark conditions. Robust differences between the genotypes were revealed when the mice were transferred from light-dark to constant darkness conditions. In addition, the ability of the VIP KO mice to encode changes in photoperiod was examined. Strikingly, the behavioral and physiological rhythms of VIP KO mice showed no adaptation to short or long photoperiods. The data indicate that the intact circadian system can compensate for some of the consequences of the loss of VIP, whereas this peptide is indispensable for endogenous encoding of seasonal information.
    European Journal of Neuroscience 04/2012; 35(9):1466-74. DOI:10.1111/j.1460-9568.2012.08054.x · 3.18 Impact Factor
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