2,033 research outputs found

    Transient Resetting: A Novel Mechanism for Synchrony and Its Biological Examples

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    The study of synchronization in biological systems is essential for the understanding of the rhythmic phenomena of living organisms at both molecular and cellular levels. In this paper, by using simple dynamical systems theory, we present a novel mechanism, named transient resetting, for the synchronization of uncoupled biological oscillators with stimuli. This mechanism not only can unify and extend many existing results on (deterministic and stochastic) stimulus-induced synchrony, but also may actually play an important role in biological rhythms. We argue that transient resetting is a possible mechanism for the synchronization in many biological organisms, which might also be further used in medical therapy of rhythmic disorders. Examples on the synchronization of neural and circadian oscillators are presented to verify our hypothesis.Comment: 17 pages, 7 figure

    In Synch but Not in Step: Circadian Clock Circuits Regulating Plasticity in Daily Rhythms

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    The suprachiasmatic nucleus (SCN) is a network of neural oscillators that program daily rhythms in mammalian behavior and physiology. Over the last decade much has been learned about how SCN clock neurons coordinate together in time and space to form a cohesive population. Despite this insight, much remains unknown about how SCN neurons communicate with one another to produce emergent properties of the network. Here we review the current understanding of communication among SCN clock cells and highlight a collection of formal assays where changes in SCN interactions provide for plasticity in the waveform of circadian rhythms in behavior. Future studies that pair analytical behavioral assays with modern neuroscience techniques have the potential to provide deeper insight into SCN circuit mechanisms

    Pacemaker Heterogeneity in the Suprachiasmatic Nucleus: Origins and Network Implications

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    In mammals, the suprachiasmatic nuclei: SCN) in the ventral hypothalamus function as a circadian pacemaker, controlling daily rhythms in behavior and physiology. Together the SCN contain approximately 20,000 neurons that maintain rhythms in firing rate and gene expression. Previous studies led to the assumption that single SCN neurons are capable of self-sustained circadian rhythms. Whether and which SCN neurons can maintain cell-autonomous daily oscillations has not been extensively tested. We measured PERIOD2::LUCIFERASE expression in isolated SCN neurons over multiple days to determine if all SCN neurons were circadian. We then examined neuropeptide content of the recorded neurons. We found that when isolated physically or with a blocker of cell-cell communication, SCN neurons expressed a range of circadian periods, amplitudes, and abilities to sustain cycling. Surprisingly, most cells were sloppy oscillators, switching from rhythmic to arrhythmic or vice versa throughout their lifetime. We also found no evidence for a class of circadian-pacemaker neurons in the SCN based on neuropeptide expression. We conclude that while all SCN neurons are capable of cell-autonomous rhythms, they are intrinsically sloppy with network interactions dramatically increasing the number of circadian neurons. We next used a mathematical model of the mammalian circadian clock to determine whether rates of gene transcription, protein translation, degradation or phosphorylation might explain the ability of SCN neurons to switch between circadian and arrhythmic behaviors. We found that rhythmicity was more sensitive to the rates of protein translation and degradation. We next tested what effect having neurons with different intrinsic circadian behaviors would have on population synchrony. We simulated cells of known circadian phenotypes: e.g. arrhythmic, damped, or self-sustained) in a pattern defined by small-world network properties and varied the positions and proportions of each oscillator type. We found that increasing the number of damped oscillators or placing them in highly connected locations within the network both augmented the rate at which the network synchronized. We conclude that the SCN likely benefit from a heterogeneous population of oscillators, especially when recovering from an environmental perturbation that causes desynchrony. Finally, we generated and characterized two independent lines of transgenic mice to test the role of vasoactive intestinal polypeptide: VIP) neurons in circadian rhythmicity. These mice express Yellow Fluorescent Protein: YFP) under the control of a fragment of the VIP promoter in VIP neurons of the SCN, neocortex, olfactory bulbs, and enteric nervous system. We crossed these mice to generate a line in which VIP neurons are targeted for deletion using Cre-mediated recombination upon addition of tamoxifen. We observed successful deletion of VIP neurons in cultured SCN explants, but have no evidence to date for deletion of SCN neurons in vivo using a variety of protocols. We conclude that our construct is faithfully expressed in VIP neurons and that in vitro experiments show promising results for further study

    Live imaging of altered period1 expression in the suprachiasmatic nuclei of Vipr2−/− mice1

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    Vasoactive intestinal polypeptide and its receptor, VPAC2, play important roles in the functioning of the brain’s circadian clock in the suprachiasmatic nuclei (SCN). Mice lacking VPAC2 receptors (Vipr2−/−) show altered circadian rhythms in locomotor behavior, neuronal firing rate, and clock gene expression, however, the nature of molecular oscillations in individual cells is unclear. Here, we used real-time confocal imaging of a destabilized green fluorescent protein (GFP) reporter to track the expression of the core clock gene Per1 in live SCN-containing brain slices from wild-type (WT) and Vipr2−/− mice. Rhythms in Per1-driven GFP were detected in WT and Vipr2−/− cells, though a significantly lower number and proportion of cells in Vipr2−/− slices expressed detectable rhythms. Further, Vipr2−/− cells expressed significantly lower amplitude oscillations than WT cells. Within each slice, the phases of WT cells were synchronized whereas cells in Vipr2−/− slices were poorly synchronized. Most GFP-expressing cells, from both genotypes, expressed neither vasopressin nor vasoactive intestinal polypeptide. Pharmacological blockade of VPAC2 receptors in WT SCN slices partially mimicked the Vipr2−/− phenotype. These data demonstrate that intercellular communication via the VPAC2 receptor is important for SCN neurons to sustain robust, synchronous oscillations in clock gene expression

    Global parameter search reveals design principles of the mammalian circadian clock

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    Background: Virtually all living organisms have evolved a circadian (~24 hour) clock that controls physiological and behavioural processes with exquisite precision throughout the day/night cycle. The suprachiasmatic nucleus (SCN), which generates these ~24 h rhythms in mammals, consists of several thousand neurons. Each neuron contains a gene-regulatory network generating molecular oscillations, and the individual neuron oscillations are synchronised by intercellular coupling, presumably via neurotransmitters. Although this basic mechanism is currently accepted and has been recapitulated in mathematical models, several fundamental questions about the design principles of the SCN remain little understood. For example, a remarkable property of the SCN is that the phase of the SCN rhythm resets rapidly after a 'jet lag' type experiment, i.e. when the light/ dark (LD) cycle is abruptly advanced or delayed by several hours. Results: Here, we describe an extensive parameter optimization of a previously constructed simplified model of the SCN in order to further understand its design principles. By examining the top 50 solutions from the parameter optimization, we show that the neurotransmitters' role in generating the molecular circadian rhythms is extremely important. In addition, we show that when a neurotransmitter drives the rhythm of a system of coupled damped oscillators, it exhibits very robust synchronization and is much more easily entrained to light/dark cycles. We were also able to recreate in our simulations the fast rhythm resetting seen after a 'jet lag' type experiment. Conclusion: Our work shows that a careful exploration of parameter space for even an extremely simplified model of the mammalian clock can reveal unexpected behaviours and non-trivial predictions. Our results suggest that the neurotransmitter feedback loop plays a crucial role in the robustness and phase resetting properties of the mammalian clock, even at the single neuron level

    The roles of vasoactive intestinal polypeptide in circadian entrainment of suprachiasmatic nucleus

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    In mammalian hypothalamus, the suprachiasmatic nucleus: SCN) generates daily behavioral and physiological rhythms as a circadian pacemaker. The 20,000 SCN neurons synchronize to each other and to the ambient cues to generate coherent daily rhythms. Vasoactive intestinal polypeptide: VIP), a neuropeptide produced by SCN neurons, plays a major role in synchronizing SCN neurons to each other. Whether VIP mediates synchrony to environmental cues and how synchrony within the SCN is achieved has not been examined extensively. We recorded PERIOD::LUCIFERASE: PER2::LUC) expression from SCN explant cultures over multiple days following VIP application at different circadian time points to generate a phase response curve which reliably predicted the phase relationship between the SCN and daily increases in VIP. VIP shifted PER2::LUC rhythms in time- and dose-dependent manner. VIP rapidly increased intracellular cAMP in most SCN neurons and simultaneous antagonism of adenylate cyclase: AC) and phospholipase C: PLC) was required to block the VIP-induced phase shifts of SCN PER2 rhythms. We conclude that VIP entrains circadian timing among SCN neurons through rapid and parallel changes in AC and PLC activities. While performing the experiments mentioned above, we found that a single VIP pulse reliably reduced the PER2::LUC rhythm amplitude in the SCN explants. The amplitude reduction was dose-dependent, but not circadian. We found that the amplitude reduction was primarily explained by reduced synchrony among SCN neurons, with little effect on the amplitude of individual neurons. To test if VIP modulates the amplitude of circadian rhythm in vivo, we compared the effects of light on locomotor rhythms in wild-type and VIP-deficient mice. We found that constant light reduced the amplitude of behavioral rhythms in wild type, but not in Vip-/-, mice. Because, theoretically, reduced synchrony among oscillators can facilitate their entrainment to periodic signals, we tested if VIP accelerates entrainment of animals to an 8-h advanced light-cycle or SCN explants to a 10-h advanced temperature cycle. We found that VIP doubled the speed of circadian entrainment both in vivo and in vitro. We conclude that reduced synchrony by VIP accelerates entrainment. Finally, we characterized the spatiotemporal expression of one of the three major VIP receptors, VPAC2R, in various brain areas and SCN. We characterized the specificity of a new antibody and found moderate to weak levels of VPAC2R in cortex, hippocampus, olfactory bulb, cerebellum, arcuate nucleus in hypothalamus, amygdala and ventrolateral thalamus and high levels in the SCN. VPAC2R expression was observed from rostral to caudal SCN with stronger expression in dorsomedial area. SCN neurons expressing VIP or vasopressin all expressed VPAC2R. We found intracellular VPAC2 expression mainly along cell bodies and dendrites, but not along their axons. We found that VPAC2R levels in the SCN do not oscillate in light-dark cycles or in constant conditions. We conclude that VPAC2R presents broadly in the SCN throughout the day to mediate circadian synchrony in the SCN. Taken together, these experiments suggest that VIP signaling mediate entrainment to the daily light cycle and an altered schedule by jet lag or day night shift work through wide expression of VPAC2R in the SCN

    The Role of VIP SCN Neurons in Circadian Physiology and Behavior

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    Located in the ventral hypothalamus, the suprachiasmatic nucleus (SCN) is necessary for entraining daily rhythms in physiology and behavior to environmental cues. Though the 20,000 neurons of the SCN uniformly express GABA, they differ greatly in neuropeptide content. One anatomically and functionally distinct class of neuropeptidergic SCN neurons is vasoactive intestinal polypeptide (VIP). Expressed by approximately 10% of SCN neurons, VIP is necessary for synchronizing single-cell SCN rhythms to produce coherent output and sufficient for entrainment. However, little is known about the firing activity of these neurons releases VIP and results in circadian entrainment. We utilized multielectrode array technology and optogenetics to optically tag VIP neurons expressing Channelrhodopsin-2 (ChR2) following three days of spontaneous activity recordings. We find that VIP neurons have circadian firing rates with two distinct patterns, irregular and tonic, that constitute two separate electrophysiological classes. Using optogenetic stimulation in vitro and in vivo, we show that high frequency firing intervals are sufficient to phase shift and entrain circadian rhythms in gene expression and locomotor activity through VIP release. Interestingly, low frequency firing intervals do not phase shift the SCN in vitro and entrain behavioral rhythms more gradually. We also find that stimulation of VIP neurons can only phase delay and entrain rhythms during late subjective day and early subjective night. We conclude that VIP neurons entrain behavior in a time-of-day- and frequency- dependent manner. Complementary to testing the sufficiency of VIP neuronal firing for entrainment, we tested the necessity of VIP neurons for circadian rhythms in the adult SCN circuit. Using Cre-lox technology in vivo, we triggered adult-onset apoptosis in VIP SCN neurons. We found that over 80% of these mice retained circadian rhythms. We contrast this to Vip null mice, where over 60% lose rhythms. A majority of our mice lacking VIP neurons had decreased locomotor activity periods and increased daily onset variability, which strongly correlated with the intensity of VIP staining. In vitro, deletion of VIP neurons leads to a dramatically reduced amplitude of circadian gene expression and decreases in synchrony on the single-cell level. We conclude that the difference between adult deletion of VIP neurons and Vip null mice suggests a role for VIP in SCN development and in the developed adult circuit VIP neurons are not necessary for rhythmicity. Finally, we dissected the role of VIP SCN neurons in the daily rhythms in glucocorticoids, by characterizing the anatomy of VIP projections and testing the necessity of VIP neurons. We labeled VIP SCN neurons that project dorsally to the paraventricular nucleus of the hypothalamus (PVN) using a two-color tract tracing experiment. We concluded that a small bilateral subset of VIP SCN neurons projects to each side of the PVN. To test VIP neurons function, we deleted VIP SCN neurons in the adult and measured corticosterone rhythms under constant conditions for 2 days. We find that rhythms in corticosterone are severely dampened with the loss of VIP neurons with peak corticosterone only reaching approximately 50% of wild- type levels. We conclude that VIP SCN neurons contribute stimulatory input to the circadian rhythm in corticosterone. Taken together, these data suggest that VIP SCN neurons are a heterogeneous class of SCN neurons with multiple roles in adult SCN entrainment, development and the regulation of glucocorticoid rhythms

    Neuronal oscillations on an ultra-slow timescale: daily rhythms in electrical activity and gene expression in the mammalian master circadian clockwork

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    This is the author accepted manuscript. The final version is available from Wiley via the DOI in this record.Neuronal oscillations of the brain, such as those observed in the cortices and hippocampi of behaving animals and humans, span across wide frequency bands, from slow delta waves (0.1 Hz) to ultra-fast ripples (600 Hz). Here, we focus on ultra-slow neuronal oscillators in the hypothalamic suprachiasmatic nuclei (SCN), the master daily clock that operates on interlocking transcription-translation feedback loops to produce circadian rhythms in clock gene expression with a period of near 24 h (< 0.001 Hz). This intracellular molecular clock interacts with the cell's membrane through poorly understood mechanisms to drive the daily pattern in the electrical excitability of SCN neurons, exhibiting an up-state during the day and a down-state at night. In turn, the membrane activity feeds back to regulate the oscillatory activity of clock gene programs. In this review, we emphasise the circadian processes that drive daily electrical oscillations in SCN neurons, and highlight how mathematical modelling contributes to our increasing understanding of circadian rhythm generation, synchronisation and communication within this hypothalamic region and across other brain circuits.M.D.C.B is supported by the University ofExeter Medical School (UEMS). C.O.D’s work was partially supported bythe National Science Foundation under grant nos. DMS-1412877 and DMS-155237, and the U.S. Army Research Laboratory and the U.S. ArmyResearch Office under Grant No. W911NF-16-1-0584
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