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
    • "However, recent work suggests that transient ''phase tumbling'' [25] of the light entrainment process may be exploited for more rapid recovery from jetlag [25]. While much work has shown the importance of VIP peptidergic signaling in the SCN for maintaining robust rhythms404142 , pharmacological treatment with different concentrations of VIP, GABAergic, and vasopressin agents can also transiently weaken oscillator function, resulting in more rapid entrainment [25,434445. Temporarily weakening oscillator coupling and dephasing of rhythms appears to permit circuits to more easily reset to phase shifts, and overly robust oscillator networks block entrainment [25, 43, 44,46474849. "
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    ABSTRACT: Circadian neural circuits generate near 24-hr physiological rhythms that can be entrained by light to coordinate animal physiology with daily solar cycles. To examine how a circadian circuit reorganizes its activity in response to light, we imaged period (per) clock gene cycling for up to 6 days at single-neuron resolution in whole-brain explant cultures prepared from per-luciferase transgenic flies. We compared cultures subjected to a phase-advancing light pulse (LP) to cultures maintained in darkness (DD). In DD, individual neuronal oscillators in all circadian subgroups are initially well synchronized but then show monotonic decrease in oscillator rhythm amplitude and synchrony with time. The small ventral lateral neurons (s-LNvs) and dorsal lateral neurons (LNds) exhibit this decrease at a slower relative rate. In contrast, the LP evokes a rapid loss of oscillator synchrony between and within most circadian neuronal subgroups, followed by gradual phase retuning of whole-circuit oscillator synchrony. The LNds maintain high rhythmic amplitude and synchrony following the LP along with the most rapid coherent phase advance. Immunocytochemical analysis of PER shows that these dynamics in DD and LP are recapitulated in vivo. Anatomically distinct circadian neuronal subgroups vary in their response to the LP, showing differences in the degree and kinetics of their loss, recovery and/or strengthening of synchrony, and rhythmicity. Transient desynchrony appears to be an integral feature of light response of the Drosophila multicellular circadian clock. Individual oscillators in different neuronal subgroups of the circadian circuit show distinct kinetic signatures of light response and phase retuning. Copyright © 2015 Elsevier Ltd. All rights reserved.
    No preview · Article · Mar 2015 · Current biology: CB
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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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    • "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.
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