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Mammalian circadian clocks have a hierarchical organization, governed by the suprachiasmatic nucleus (SCN) in the hypothalamus. The brain itself contains multiple loci that maintain autonomous circadian rhythmicity, but the contribution of the non-SCN clocks to this hierarchy remains unclear. We examine circadian oscillations of clock gene expression in various brain loci and discovered that in mouse, robust, higher amplitude, relatively faster oscillations occur in the choroid plexus (CP) compared to the SCN. Our computational analysis and modeling show that the CP achieves these properties by synchronization of “twist” circadian oscillators via gap-junctional connections. Using an in vitro tissue coculture model and in vivo targeted deletion of the Bmal1 gene to silence the CP circadian clock, we demonstrate that the CP clock adjusts the SCN clock likely via circulation of cerebrospinal fluid, thus finely tuning behavioral circadian rhythms. The suprachiasmatic nucleus (SCN) has been thought of as the master circadian clock, but peripheral circadian clocks do exist. Here, the authors show that the choroid plexus displays oscillations more robust than the SCN and that can be described as a Poincaré oscillator with negative twist.

Both the environment and our body keep changing dynamically. Hence, ensuring movement precision requires adaptation to multiple demands occurring simultaneously. Here we show that the cerebellum performs the necessary multi-dimensional computations for the flexible control of different movement parameters depending on the prevailing context. This conclusion is based on the identification of a manifold-like activity in both mossy fibers (MFs, network input) and Purkinje cells (PCs, output), recorded from monkeys performing a saccade task. Unlike MFs, the PC manifolds developed selective representations of individual movement parameters. Error feedback-driven climbing fiber input modulated the PC manifolds to predict specific, error type-dependent changes in subsequent actions. Furthermore, a feed-forward network model that simulated MF-to-PC transformations revealed that amplification and restructuring of the lesser variability in the MF activity is a pivotal circuit mechanism. Therefore, the flexible control of movements by the cerebellum crucially depends on its capacity for multi-dimensional computations. Moving precisely in natural environments requires adapting to multiple demands arising dynamically. Here, the authors show that the cerebellum’s capacity for multidimensional computations allows it to flexibly control multiple movement parameters guaranteeing movement precision.

The mammalian suprachiasmatic nucleus (SCN) forms not only the master circadian clock but also a seasonal clock. This neural network of ∼10,000 circadian oscillators encodes season-dependent day-length changes through a largely unknown mechanism. We show that region-intrinsic changes in the SCN fine-tune the degree of network synchrony and reorganize the phase relationship among circadian oscillators to represent day length. We measure oscillations of the clock geneBmal1, at single-cell and regional levels in cultured SCN explanted from animals raised under short or long days. Coupling estimation using the Kuramoto framework reveals that the network has couplings that can be both phase-attractive (synchronizing) and -repulsive (desynchronizing). The phase gap between the dorsal and ventral regions increases and the overall period of the SCN shortens with longer day length. We find that one of the underlying physiological mechanisms is the modulation of the intracellular chloride concentration, which can adjust the strength and polarity of the ionotropic GABAA-mediated synaptic input.We show that increasing day-length changes the pattern of chloride transporter expression, yielding more excitatory GABA synaptic input, and that blocking GABAAsignaling or the chloride transporter disrupts the unique phase and period organization induced by the day length. We test the consequences of this tunable GABA coupling in the context of excitation–inhibition balance through detailed realistic modeling. These results indicate that the network encoding of seasonal time is controlled by modulation of intracellular chloride, which determines the phase relationship among and period difference between the dorsal and ventral SCN.

Enhancing adult neurogenesis in the brain has been suggested as a potential therapeutic strategy for AD. We developed a screening platform, ATRIVIEW ® , for molecules that activate neuronal differentiation of adult mouse NSCs. The most potent hit from an FDA-approved drug library was SNR1611 (trametinib), a selective MEK1/2 inhibitor. We found that trametinib increases the levels of P15 INK4b and Neurog2, suggesting a mechanism by which MEK1/2 inhibition induces neuronal differentiation. Oral administration of trametinib increased adult neurogenesis in the dentate gyrus and subventricular zone of the 5XFAD AD mouse model. Surprisingly, we also found that trametinib enhanced adult neurogenesis in the cortex. Consequently, trametinib rescued AD pathologies such as neuronal loss and cognitive impairment in 5XFAD mice. Finally, trametinib induced neurogenic differentiation of NSCs derived from AD patient iPSCs, which suggests its potential therapeutic application. Altogether, we suggest that restoration of endogenous adult neurogenesis by trametinib may be a promising therapeutic approach to AD. Trametinib: A Surprising Key in Alzheimer’s Disease Battle “Trametinib, a MEK1/2 inhibitor, promotes adult neurogenesis in an Alzheimer’s disease mouse model and human iPSC-derived neural stem cells.\" Researchers have discovered that trametinib, a MEK1/2 inhibitor, can enhance adult neurogenesis and replenish neurons in brain areas where neurodegeneration most affects Alzheimer’s disease (AD). The study found that trametinib induced neuronal differentiation of adult neural stem cells and restored impaired neurogenesis in the hippocampus and subventricular zone of the AD model mice, in addition to inducing adult cortical neurogenesis. It also demonstrated trametinib’s potential for inducing neurogenic differentiation in AD patient-induced pluripotent stem cells (iPSCs)-derived NSCs. These findings suggest that trametinib could be a promising therapeutic approach for treating AD and other neurodegenerative diseases by promoting adult neurogenesis.

Both spike rate and timing can transmit information in the brain. Phase response curves (PRCs) quantify how a neuron transforms input to output by spike timing. PRCs exhibit strong firing-rate adaptation, but its mechanism and relevance for network output are poorly understood. Using our Purkinje cell (PC) model, we demonstrate that the rate adaptation is caused by rate-dependent subthreshold membrane potentials efficiently regulating the activation of Na + channels. Then, we use a realistic PC network model to examine how rate-dependent responses synchronize spikes in the scenario of reciprocal inhibition-caused high-frequency oscillations. The changes in PRC cause oscillations and spike correlations only at high firing rates. The causal role of the PRC is confirmed using a simpler coupled oscillator network model. This mechanism enables transient oscillations between fast-spiking neurons that thereby form PC assemblies. Our work demonstrates that rate adaptation of PRCs can spatio-temporally organize the PC input to cerebellar nuclei.

Activity of sensory and motor cortices is essential for sensorimotor integration. In particular, coherence between these areas may indicate binding of critical functions like perception, motor planning, action, or sleep. Evidence is accumulating that cerebellar output modulates cortical activity and coherence, but how, when, and where it does so is unclear. We studied activity in and coherence between S1 and M1 cortices during whisker stimulation in the absence and presence of optogenetic Purkinje cell stimulation in crus 1 and 2 of awake mice, eliciting strong simple spike rate modulation. Without Purkinje cell stimulation, whisker stimulation triggers fast responses in S1 and M1 involving transient coherence in a broad spectrum. Simultaneous stimulation of Purkinje cells and whiskers affects amplitude and kinetics of sensory responses in S1 and M1 and alters the estimated S1–M1 coherence in theta and gamma bands, allowing bidirectional control dependent on behavioral context. These effects are absent when Purkinje cell activation is delayed by 20 ms. Focal stimulation of Purkinje cells revealed site specificity, with cells in medial crus 2 showing the most prominent and selective impact on estimated coherence, i.e., a strong suppression in the gamma but not the theta band. Granger causality analyses and computational modeling of the involved networks suggest that Purkinje cells control S1–M1 phase consistency predominantly via ventrolateral thalamus and M1. Our results indicate that activity of sensorimotor cortices can be dynamically and functionally modulated by specific cerebellar inputs, highlighting a widespread role of the cerebellum in coordinating sensorimotor behavior.

The granular layer, which mainly consists of granule and Golgi cells, is the first stage of the cerebellar cortex and processes spatiotemporal information transmitted by mossy fiber inputs with a wide variety of firing patterns. To study its dynamics at multiple time scales in response to inputs approximating real spatiotemporal patterns, we constructed a large-scale 3D network model of the granular layer. Patterned mossy fiber activity induces rhythmic Golgi cell activity that is synchronized by shared parallel fiber input and by gap junctions. This leads to long distance synchrony of Golgi cells along the transverse axis, powerfully regulating granule cell firing by imposing inhibition during a specific time window. The essential network mechanisms, including tunable Golgi cell oscillations, on-beam inhibition and NMDA receptors causing first winner keeps winning of granule cells, illustrate how fundamental properties of the granule layer operate in tandem to produce (1) well timed and spatially bound output, (2) a wide dynamic range of granule cell firing and (3) transient and coherent gating oscillations. These results substantially enrich our understanding of granule cell layer processing, which seems to promote spatial group selection of granule cell activity as a function of timing of mossy fiber input.

The synchronization of multiple oscillators serves as the central mechanism for maintaining stable circadian rhythms in physiology and behavior. Aging and disease can disrupt synchronization, leading to changes in the periodicity of circadian activities. While our understanding of the circadian clock under synchronization has advanced significantly, less is known about its behavior outside synchronization, which can also fall within a predictable domain. These states not only impact the stability of the rhythms but also modulate the period length. In C57BL/6 mice, aging, diseases, and removal of peripheral circadian oscillators often result in lengthened behavioral circadian periods. Here, we show that these changes can be explained by a surprisingly simple mathematical relationship: the frequency is the reciprocal of the period, and its distribution becomes skewed when the period distribution is symmetric. The synchronized frequency of a population in the skewed distribution and the macroscopic frequency of combined oscillators differ, accounting for some of the atypical circadian period outputs observed in networks without synchronization. Building on this finding, we investigate the dynamics of circadian outputs in the context of aging and disease, where synchronization is weakened.

Purkinje cells (PC), the sole output neurons of the cerebellar cortex, encode sensorimotor information, but how they do it remains a matter of debate. Here we show that PCs use a multiplexed spike code. Synchrony/spike time and firing rate encode different information in behaving monkeys during saccadic eye motion tasks. Using the local field potential (LFP) as a probe of local network activity, we found that infrequent pause spikes, which initiated or terminated intermittent pauses in simple spike trains, provide a temporally reliable signal for eye motion onset, with strong phase-coupling to the β/γ band LFP. Concurrently, regularly firing, non-pause spikes were weakly correlated with the LFP, but were crucial to linear encoding of eye movement kinematics by firing rate. Therefore, PC spike trains can simultaneously convey information necessary to achieve precision in both timing and continuous control of motion. The cerebellum is a part of the brain that uses information from the senses to coordinate movement. Cells called Purkinje neurons in the cerebellum produce the final ‘output’ of its cortex. Therefore, Purkinje neurons have to communicate precise information about different aspects of the movement, such as its speed and timing. This information is likely to be represented by patterns of electrical activity within Purkinje neurons, but these patterns are still not fully understood. Hong et al. recorded and analyzed electrical ‘spikes’, the output activity of Purkinje neurons, while monkeys made rapid eye movements. The recordings showed that occasional pauses in the otherwise regularly firing spikes of Purkinje neurons signaled the start of the eye movements. The pauses were accompanied by a sharp change in the local field potential, another electrical signal that comes from many neurons in the neighborhood. In the same cells, the rate of regularly firing spikes increased and decreased with the direction and speed of eye movements, following a simple relationship and independently of the local field potential. Purkinje neurons therefore appear to use both the timing and the rate of their spiking activity to represent movement. This resolves conflicting reports in the literature claiming that either rates of spiking or their timing code essential information about movements: both are important. This way of representing information by combining more than one source is known as multiplexed coding. Next, experiments recording electrical activity from many cells in the cerebellum at the same time are needed to find out how multiple Purkinje neurons can pause their spiking activity at the same time. Future experiments should also uncover how pauses in spiking and firing rates change with learning.

We present the concept of a novel thermal power plant process in conjunction with low-temperature selective catalytic reduction (SCR). This process can be employed to achieve modern standards for NOx emissions and solve problems related to post-gas cleaning processes, such as thermal fatigue, catalyst damage, and an increase in differential pressure in the boiler. Therefore, this study is aimed at evaluating the performance of a novel flue-gas cleaning process for use in a thermal power plant, where a low-temperature SCR is implemented, along with the existing SCR. We developed a process model for a large-scale power plant, in which the thermal power plant was divided into a series of heat exchanger block models. The mass and energy balances were solved by considering the heat transfer interaction between the hot and cold sides to obtain the properties of each material flow. Using the process model, we performed a simulation of the new process. New optimal operating conditions were derived, and the effects that the new facilities have on the existing process were evaluated. The results show that the new process is feasible in terms of operating stability and cost, as well as showing an increase in the boiler thermal efficiency of up to 1.3%.