Hiroshi Kori

Oscillatory Control of Factors Determining Multipotency and Fate in Mouse Neural Progenitors

Oscillation Stabilizes the Progenitor State Transcription factors regulate fate choice between different neural lineages, but the same transcription factors are also expressed in neural progenitor cells. Imayoshi et al. (p. 1203, published online 31 October) analyzed the details of expression of several transcription factors in mouse neural cells. In neural progenitor cells, several different transcription factors were expressed in an oscillatory manner, whereas differentiated neurons stably expressed a single lineage-specific factor. During neural development, the differentiated state correlates with sustained expression of a single fate-determination factor. The basic helix-loop-helix transcription factors Ascl1/Mash1, Hes1, and Olig2 regulate fate choice of neurons, astrocytes, and oligodendrocytes, respectively. These same factors are coexpressed by neural progenitor cells. Here, we found by time-lapse imaging that these factors are expressed in an oscillatory manner by mouse neural progenitor cells. In each differentiation lineage, one of the factors becomes dominant. We used optogenetics to control expression of Ascl1 and found that, although sustained Ascl1 expression promotes neuronal fate determination, oscillatory Ascl1 expression maintains proliferating neural progenitor cells. Thus, the multipotent state correlates with oscillatory expression of several fate-determination factors, whereas the differentiated state correlates with sustained expression of a single factor.

Mice Genetically Deficient in Vasopressin V1a and V1b Receptors Are Resistant to Jet Lag

Resetting the Circadian Clock Fatigue and other symptoms of jet lag arise when the bodys internal circadian clock is out of sync with environmental light-dark cycles. Studying genetically modified mice lacking two receptors for the peptide hormone vasopressin under experimental conditions simulating jet lag, Yamaguchi et al. (p. 85; see the Perspective by Hastings) concluded that vasopressin signaling in the suprachiasmatic nucleus (SCN)—a region of the brain known to control circadian rhythms—impedes adjustment to the environmental clock. Infusion of vasopressin receptor antagonists directly into the SCN of wild-type mice accelerated their recovery from jet lag, suggesting that this pathway may merit further investigation as a pharmacological target for treating jet lag. In mice, the pace of recovery from jet lag is partly determined by vasopressin signaling in a certain region of the brain. [Also see Perspective by Hastings] Jet-lag symptoms arise from temporal misalignment between the internal circadian clock and external solar time. We found that circadian rhythms of behavior (locomotor activity), clock gene expression, and body temperature immediately reentrained to phase-shifted light-dark cycles in mice lacking vasopressin receptors V1a and V1b (V1a–/–V1b–/–). Nevertheless, the behavior of V1a–/–V1b–/– mice was still coupled to the internal clock, which oscillated normally under standard conditions. Experiments with suprachiasmatic nucleus (SCN) slices in culture suggested that interneuronal communication mediated by V1a and V1b confers on the SCN an intrinsic resistance to external perturbation. Pharmacological blockade of V1a and V1b in the SCN of wild-type mice resulted in accelerated recovery from jet lag, which highlights the potential of vasopressin signaling as a therapeutic target for management of circadian rhythm misalignment, such as jet lag and shift work.

Engineering Complex Dynamical Structures: Sequential Patterns and Desynchronization

We used phase models to describe and tune complex dynamic structures to desired states; weak, nondestructive signals are used to alter interactions among nonlinear rhythmic elements. Experiments on electrochemical reactions on electrode arrays were used to demonstrate the power of mild model-engineered feedback to achieve a desired response. Applications are made to the generation of sequentially visited dynamic cluster patterns similar to reproducible sequences seen in biological systems and to the design of a nonlinear antipacemaker for the destruction of pathological synchronization of a population of interacting oscillators.

Circadian regulation of intracellular G-protein signalling mediates intercellular synchrony and rhythmicity in the suprachiasmatic nucleus

Synchronous oscillations of thousands of cellular clocks in the suprachiasmatic nucleus (SCN), the circadian centre, are coordinated by precisely timed cell–cell communication, the principle of which is largely unknown. Here we show that the amount of RGS16 (regulator of G protein signalling 16), a protein known to inactivate Gαi, increases at a selective circadian time to allow time-dependent activation of intracellular cyclic AMP signalling in the SCN. Gene ablation of Rgs16 leads to the loss of circadian production of cAMP and as a result lengthens circadian period of behavioural rhythm. The temporally precise regulation of the cAMP signal by clock-controlled RGS16 is needed for the dorsomedial SCN to maintain a normal phase-relationship to the ventrolateral SCN. Thus, RGS16-dependent temporal regulation of intracellular G protein signalling coordinates the intercellular synchrony of SCN pacemaker neurons and thereby defines the 24 h rhythm in behaviour.

Slow switching in globally coupled oscillators: robustness and occurrence through delayed coupling

The phenomenon of slow switching in populations of globally coupled oscillators is discussed. This characteristic collective dynamics, which was first discovered in a particular class of the phase oscillator model, is a result of the formation of a heteroclinic loop connecting a pair of clustered states of the population. We argue that the same behavior can arise in a wider class of oscillator models with the amplitude degree of freedom. We also argue how such heteroclinic loops arise inevitably and persist robustly in a homogeneous population of globally coupled oscillators. Although a heteroclinic loop might seem to arise only exceptionally, we find that it appears rather easily by introducing time delay into a population which would otherwise exhibit perfect phase synchrony. We argue that the appearance of the heteroclinic loop induced by the delayed coupling is then characterized by transcritical and saddle-node bifurcations. Slow switching arises when a system with a heteroclinic loop is weakly perturbed. This will be demonstrated with a vector model by applying weak noises. Other types of weak symmetry-breaking perturbations can also cause slow switching.

Formation of feedforward networks and frequency synchrony by spike-timing-dependent plasticity

Spike-timing-dependent plasticity (STDP) with asymmetric learning windows is commonly found in the brain and useful for a variety of spike-based computations such as input filtering and associative memory. A natural consequence of STDP is establishment of causality in the sense that a neuron learns to fire with a lag after specific presynaptic neurons have fired. The effect of STDP on synchrony is elusive because spike synchrony implies unitary spike events of different neurons rather than a causal delayed relationship between neurons. We explore how synchrony can be facilitated by STDP in oscillator networks with a pacemaker. We show that STDP with asymmetric learning windows leads to self-organization of feedforward networks starting from the pacemaker. As a result, STDP drastically facilitates frequency synchrony. Even though differences in spike times are lessened as a result of synaptic plasticity, the finite time lag remains so that perfect spike synchrony is not realized. In contrast to traditional mechanisms of large-scale synchrony based on mutual interaction of coupled neurons, the route to synchrony discovered here is enslavement of downstream neurons by upstream ones. Facilitation of such feedforward synchrony does not occur for STDP with symmetric learning windows.

Entrainment of randomly coupled oscillator networks by a pacemaker

Entrainment by a pacemaker, representing an element with a higher frequency, is numerically investigated for several classes of random networks which consist of identical phase oscillators. We find that the entrainment frequency window of a network decreases exponentially with its depth, defined as the mean forward distance of the elements from the pacemaker. Effectively, only shallow networks can thus exhibit frequency locking to the pacemaker. The exponential dependence is also derived analytically as an approximation for large random asymmetric networks.

Decentralised control of material or traffic flows in networks using phase-synchronisation

We present a self-organising, decentralised control method for material flows in networks. The concept applies to networks where time sharing mechanisms between conflicting flows in nodes are required and where a coordination of these local switches on a system-wide level can improve the performance. We show that, under certain assumptions, the control of nodes can be mapped to a network of phase-oscillators.

Oscillatory control of Delta-like1 in cell interactions regulates dynamic gene expression and tissue morphogenesis

Notch signaling regulates tissue morphogenesis through cell-cell interactions. The Notch effectors Hes1 and Hes7 are expressed in an oscillatory manner and regulate developmental processes such as neurogenesis and somitogenesis, respectively. Expression of the mRNA for the mouse Notch ligand Delta-like1 (Dll1) is also oscillatory. However, the dynamics of Dll1 protein expression are controversial, and their functional significance is unknown. Here, we developed a live-imaging system and found that Dll1 protein expression oscillated in neural progenitors and presomitic mesoderm cells. Notably, when Dll1 expression was accelerated or delayed by shortening or elongating the Dll1 gene, Dll1 oscillations became severely dampened or quenched at intermediate levels, as modeled mathematically. Under this condition, Hes1 and Hes7 oscillations were also dampened. In the presomitic mesoderm, steady Dll1 expression led to severe fusion of somites and their derivatives, such as vertebrae and ribs. In the developing brain, steady Dll1 expression inhibited proliferation of neural progenitors and accelerated neurogenesis, whereas optogenetic induction of Dll1 oscillation efficiently maintained neural progenitors. These results indicate that the appropriate timing of Dll1 expression is critical for the oscillatory networks and suggest the functional significance of oscillatory cell-cell interactions in tissue morphogenesis.

Self-organization of feed-forward structure and entrainment in excitatory neural networks with spike-timing-dependent plasticity.

Spike-timing dependent plasticity (STDP) is an organizing principle of biological neural networks. While synchronous firing of neurons is considered to be an important functional block in the brain, how STDP shapes neural networks possibly toward synchrony is not entirely clear. We examine relations between STDP and synchronous firing in spontaneously firing neural populations. Using coupled heterogeneous phase oscillators placed on initial networks, we show numerically that STDP prunes some synapses and promotes formation of a feedforward network. Eventually a pacemaker, which is the neuron with the fastest inherent frequency in our numerical simulations, emerges at the root of the feedforward network. In each oscillatory cycle, a packet of neural activity is propagated from the pacemaker to downstream neurons along layers of the feedforward network. This event occurs above a clear-cut threshold value of the initial synaptic weight. Below the threshold, neurons are self-organized into separate clusters each of which is a feedforward network.