Internal Timing Mechanism Research Articles

Polarization-Dominated Internal Timing Mechanism in a Ferroelectric Second-Order Memristor

Second-order memristors are considered as ideal synaptic emulators for their capability of exhibiting ${\mathrm{Ca}}^{2+}$-like dynamics. Recently, ferroelectric second-order memristors were developed, but whether their temporal conductance evolution is related to polarization dynamics remains unclear owing to the difficulty in directly measuring polarization in these devices. This issue is addressed here by using a ferroelectric diode (FD) that shows both second-order memristive behavior and well-shaped polarization-voltage hysteresis loops. It is demonstrated that the resistance-state change in the FD is triggered by polarization switching, arising from polarization-controlled Schottky emission. Moreover, concurrent conductance decay and polarization relaxation are observed, and their correlation is quantitatively evidenced, suggesting that conductance decay is caused by the polarization-relaxation-induced increase in the Schottky barrier height. Using polarization relaxation as an internal timing mechanism, our FD-based second-order memristor faithfully emulates various synaptic functions, where short-term plasticity is indispensable, including excitatory postsynaptic current, paired-pulse facilitation, the transition from short-term plasticity to long-term plasticity, learning experience, and associative learning. Our study not only reveals a polarization-dominated internal timing mechanism in the FD-based second-order memristor, but also demonstrates that such a device is a promising building block for biorealistic neuromorphic systems.

Advances in circadian rhythms in oral maxillofacial tissues and oral-related diseases

Circadian rhythm is an internal autonomous timing mechanism formed by the body in response to changes of external environment. It participates in the regulations of various physiological activities, affecting the formation and outcome of various diseases in the human body. This paper summarizes the changes of local tissue rhythms in common disease states, such as oral and maxillofacial malformations, inflammation and malignant tumors. The importance of circadian clock system to the activities of oral and maxillofacial tissues are dialectically analyzed, mainly on the mechanisms of action in maintaining oral health and in affecting the processes of common oral diseases and oral-related systemic diseases. At the same time, chronological therapy and new strategies of prevention and treatment for oral-related diseases based on the changes in tissue rhythm are summarized and prospected to provide new ideas for maintaining oral and systemic health.

What about the role of the cerebellum in music-associated functional recovery? A secondary EEG analysis of a randomized clinical trial in patients with Parkinson disease

Rhythmic Auditory Stimulation (RAS) has been shown to be of help in an effective gait training of people with idiopathic Parkinson's disease (PD). The cerebellum may play an important role in RAS aftereffects by compensating the detrimental internal clock for automatic and rhythmic motricity. However, the neurophysiological mechanisms underlying RAS aftereffects are still poorly understood. In the present study, we tested the contribution of the cerebellum to RAS-based gait training aftereffects in people with PD by examining cerebellum-cerebral connectivity indices using standard EEG recording. We enrolled 50 patients with PD who were randomly assigned to two different modalities of treadmill gait training using GaitTrainer3 with and without RAS (non_RAS) during an 8-week training program. We measured clinical and kinematic gait indices and electrophysiological data (standard EEG recording during walking on GaitTrainer3) of both the gait trainings. We found that the greater improvement in gait performance following RAS than non_RAS training, as per clinical and kinematic assessment, was paralleled by a more evident reshape of cerebellum-brain functional connectivity with regard to specific brain areas (pre-motor, sensorimotor and temporal cortices) and gait-cycle phases (mainly 25–75% of the gait cycle duration). These findings suggest that the cerebellum mediates the reshape of sensorimotor rhythms and fronto-centroparietal connectivity in relation to specific gait-cycle phases. This may be consistent with a recovery of the internal timing mechanisms generating and controlling motor rhythmicity, eventually improving gait performance. The precise definition of the cerebellar role to gait functional recovery in people with PD may be crucial to create patient-tailored rehabilitative approaches.

Tuning Resistive Switching Behavior by Controlling Internal Ionic Dynamics for Biorealistic Implementation of Synaptic Plasticity

AbstractMemristive devices have demonstrated rich switching behaviors that closely resemble synaptic functions and provide a building block to construct efficient neuromorphic systems. It is demonstrated that resistive switching effects are controlled not only by the external field, but also by the dynamics of various internal state variables that facilitate the ionic processes. The internal temperature, for example, works as a second‐state variable to regulate the ion motion and provides the internal timing mechanism for the native implementation of timing‐ and rate‐based learning rules such as spike timing dependent plasticity (STDP). In this work, it is shown that the 2nd state‐variable in a Ta2O5‐based memristor, its internal temperature, can be systematically engineered by adjusting the material properties and device structure, leading to tunable STDP characteristics with different time constants. When combined with an artificial post‐synaptic neuron, the 2nd‐order memristor synapses can spontaneously capture the temporal correlation in the input streaming events.

Introduction to biological rhythms: A brief history of chronobiology and its relevance to parasite immunology.

Almost every living organism on earth is exposed to a fluctuating environment, for example, light:dark cycles, food availability and seasonal photoperiods. Most species have therefore evolved internal timing mechanisms allowing them to anticipate these rhythmic environmental changes, obtaining a survival advantage. Circadian (24h) rhythms, in particular, regulate multiple aspects of physiology, including sleep/wake activity, feeding rhythms and immune function. Recent studies have identified circadian rhythms in symptoms of parasite infections, rhythms in parasite schizogony and evidence that certain parasites can manipulate host rhythms. Furthermore, efficacy of anti-parasite medications can also be modulated by timing of drug administration. Understanding the interactions between host rhythms, parasite rhythms and disease severity is crucial to fully understand how to combat infections and reduce pathology. The aim of this review is, therefore, to provide an introduction to the field of biological rhythms, give a brief history of chronobiology research and discuss the relevance of biological rhythms to parasite immunology.

Effects of light cycle on circadian feeding activity and digestive physiology in Haliotis discus hannai

The abalone Haliotis discus hannai is a typical nocturnal animal. It generally feeds and moves at night but evades light by hiding in the shade during the day. However, the effects of different light cycles on the feeding physiology and potential molecular mechanisms responsible for such effects in H. discus hannai have not yet been reported. We examined the feeding patterns of abalones under different light (L)/dark (D) cycles (0 L:24D, 12 L:12D, 24 L:0D) using an infrared camera and analyzed the relationships between circadian digestive enzyme activities, gene expression levels of neuropeptide Y (NPY) and its receptor (NPYR), which can promote appetite, and feeding rhythms. Feeding in abalones, including searching for food and, food capture and intake, was examined by observation of videos. The percentage of abalones feeding under different light/dark cycles had two peaks, at 20:00–22:00 and 02:00–04:00. The ingestion rate was significantly higher in abalones maintained under 12 L:12D compared with 24 L:0D conditions. The percentage of feeding individuals and food intake were significantly lower in the “daytime” compared with at “night” irrespective of the light/dark cycle, suggesting the existence of an independent internal timing mechanism and the possible involvement of circadian clock genes in the regulation of periodic feeding activity in abalones. In abalones maintained under 12 L:12D and 24 L:0D cycles, protease, cellulase, and α-amylase activities started to increase from 18:00, 2 h before the first peak of food intake. Expression levels of NPY peaked at 20:00 and expression levels of NPYR increased again at 04:00, suggesting that NPY and NPYR might be induced before and after the two peak periods of food intake in abalones, respectively. These findings demonstrate the feeding rhythm and ingestion rate of abalones under different light/dark cycles, as well as the relationships among digestive enzyme activities, gene expression levels of NPY and NPYR, and feeding activity, which in turn provides a useful reference for the development of optimal feeding strategies and improved food utilization in abalone aquaculture production.

The Peak Interval Procedure in Rodents: A Tool for Studying the Neurobiological Basis of Interval Timing and Its Alterations in Models of Human Disease.

Animals keep track of time intervals in the seconds to minutes range with, on average, high accuracy but substantial trial-to-trial variability. The ability to detect the statistical signatures of such timing behavior is an indispensable feature of a good and theoretically-tractable testing procedure. A widely used interval timing procedure is the peak interval (PI) procedure, where animals learn to anticipate rewards that become available after a fixed delay. After learning, they cluster their responses around that reward-availability time. The in-depth analysis of such timed anticipatory responses leads to the understanding of an internal timing mechanism, that is, the processing dynamics and systematic biases of the brain's clock. This protocol explains in detail how the PI procedure can be implemented in rodents, from training through testing to analysis. We showcase both trial-by-trial and trial-averaged analytical methods as a window into these internal processes. This protocol has the advantages of capturing timing behavior in its full-complexity in a fashion that allows for a theoretical treatment of the data.

Walking to your right music: a randomized controlled trial on the novel use of treadmill plus music in Parkinson\u2019s disease

BackgroundRhythmic Auditory Stimulation (RAS) can compensate for the loss of automatic and rhythmic movements in patients with idiopathic Parkinson’s disease (PD). However, the neurophysiological mechanisms underlying the effects of RAS are still poorly understood. We aimed at identifying which mechanisms sustain gait improvement in a cohort of patients with PD who practiced RAS gait training.MethodsWe enrolled 50 patients with PD who were randomly assigned to two different modalities of treadmill gait training using GaitTrainer3 with and without RAS (non_RAS) during an 8-week training program. We measured clinical, kinematic, and electrophysiological effects of both the gait trainings.ResultsWe found a greater improvement in Functional Gait Assessment (p < 0.001), Tinetti Falls Efficacy Scale (p < 0.001), Unified Parkinson Disease Rating Scale (p = 0.001), and overall gait quality index (p < 0.001) following RAS than non_RAS training. In addition, the RAS gait training induced a stronger EEG power increase within the sensorimotor rhythms related to specific periods of the gait cycle, and a greater improvement of fronto-centroparietal/temporal electrode connectivity than the non_RAS gait training.ConclusionsThe findings of our study suggest that the usefulness of cueing strategies during gait training consists of a reshape of sensorimotor rhythms and fronto-centroparietal/temporal connectivity. Restoring the internal timing mechanisms that generate and control motor rhythmicity, thus improving gait performance, likely depends on a contribution of the cerebellum. Finally, identifying these mechanisms is crucial to create patient-tailored, RAS-based rehabilitative approaches in PD.Trial registrationNCT03434496. Registered 15 February 2018, retrospectively registered.

Humans derive task expectancies from sub-second and supra-second interval durations.

Recent studies in the field of task switching have shown that humans can base expectancies for tasks on temporal cues. When tasks are predictable based on the duration of the preceding pre-target interval, humans implicitly adapt to this predictability, indicated by better performance in trials with validly compared to invalidly predicted tasks. Yet, it is not clear which internal timing mechanisms are involved. Previous research has suggested that intervals from the sub- and supra-second range are processed by distinct cognitive timing systems. As earlier studies on temporally predictable task switching have used predictive intervals stemming from both ranges, it was not yet clear if the time-based expectancy effect was driven by just one of the two internal timing systems. The present study used clearly sub-second intervals (10ms and 500ms) in Experiment 1, while clearly supra-second intervals (1500ms and 3000ms) were used in Experiment 2. Substantial adaptation effects were observed in both experiments, showing that sub- as well as supra-second timing systems are involved in time-based expectancies for tasks. The present findings offer important implications for our theoretical understanding of the internal timing mechanisms involved in time-based task expectancy.

SAL1-PAP retrograde signalling extends circadian period by reproducing the loss of exoribonuclease (XRN) activity

ABSTRACTPlants have developed an internal timing mechanism, the circadian system, that serves to synchronise physiological and metabolic functions with daily cues such as dawn and dusk, and provides plants with an advantage in adapting to changing and challenging conditions. We have recently shown that the SAL1-PAP-XRN retrograde signalling pathway, which is proposed to regulate plant responses under stress conditions, also acts within the circadian system. Here we provide further evidence of circadian regulation by SAL1-PAP-XRN signalling, thereby affirming a link between molecular timekeeping and abiotic stress response mechanisms.

Circadian clocks of both plants and pollinators influence flower seeking behavior of the pollinator hawkmoth Manduca sexta

Most plant-pollinator interactions occur during specific periods during the day. To facilitate these interactions, many flowers are known to display their attractive qualities, such as scent emission and petal opening, in a daily rhythmic fashion. However, less is known about how the internal timing mechanisms (the circadian clocks) of plants and animals influence their daily interactions. We examine the role of the circadian clock in modulating the interaction between Petunia and one of its pollinators, the hawkmoth Manduca sexta. We find that desynchronization of the Petunia circadian clock affects moth visitation preference for Petunia flowers. Similarly, moths with circadian time aligned to plants show stronger flower-foraging activities than moths that lack this alignment. Moth locomotor activity is circadian clock-regulated, although it is also strongly repressed by light. Moths show a time-dependent burst increase in flight activity during subjective night. In addition, moth antennal responsiveness to the floral scent compounds exhibits a 24-hour rhythm in both continuous light and dark conditions. This study highlights the importance of the circadian clocks in both plants and animals as a crucial factor in initiating specialized plant-pollinator relationships.

NAMPT-Mediated NAD Biosynthesis as the Internal Timing Mechanism: In NAD+ World, Time Is Running in Its Own Way.

The biological age of organisms differs from the chronological age and is determined by internal aging clock(s). How cells estimate time on a scale of 24 hours is relatively well studied; however, how biological time is measured by cells, tissues, organs, or organisms in longer time periods (years and decades) is largely unknown. What is clear and widely agreed upon is that the link to age and age-related diseases is not chronological, as it does not depend on a fixed passage of time. Rather, this link depends on the biological age of an individual cell, tissue, organ, or organism and not on time in a strictly chronological sense. Biological evolution does not invent new methods as often as improving upon already existing ones. It should be easier to evolve and remodel the existing (circadian) time clock mechanism to use it for measurement or regulation of longer time periods than to invent a new time mechanism/clock. Specifically, it will be demonstrated that the circadian clock can also be used to regulate circannual or even longer time periods. Nicotinamide phosphoribosyltransferase (NAMPT)-mediated nicotinamide adenine dinucleotide (NAD+) levels, being regulated by the circadian clock, might be the missing link between aging, cell cycle control, DNA damage repair, cellular metabolism and the aging clock, which is responsible for the biological age of an organism. The hypothesis that NAMPT/NAD+/SIRT1 might represent the time regulator that determines the organismal biological age will be presented. The biological age of tissues and organs might be regulated and synchronized through eNAMPT blood secretion. The "NAD World 2.0" concept will be upgraded with detailed insights into mechanisms that regulate NAD+-mediated aging clock ticking, the duration and amplitude of which are responsible for the aging rate of humans.

The impact of daytime light exposures on sleep and mood in office workers

BackgroundBy affecting the internal timing mechanisms of the brain, light regulates human physiology and behavior, perhaps most notably the sleep–wake cycle. Humans spend over 90% of their waking hours indoors, yet light in the built environment is not designed to affect circadian rhythms. ObjectiveUsing a device calibrated to measure light that is effective for the circadian system (circadian-effective light), collect personal light exposures in office workers and relate them to their sleep and mood. SettingThe research was conducted in 5 buildings managed by the US General Services Administration. ParticipantsThis study recruited 109 participants (69 females), of whom 81 (54 females) participated in both winter and summer. MeasurementsSelf-reported measures of mood and sleep, and objective measures of circadian-effective light and activity rhythms were collected for 7 consecutive days. ResultsCompared to office workers receiving low levels of circadian-effective light in the morning, receiving high levels in the morning is associated with reduced sleep onset latency (especially in winter), increased phasor magnitudes (a measure of circadian entrainment), and increased sleep quality. High levels of circadian-effective light during the entire day are also associated with increased phasor magnitudes, reduced depression, and increased sleep quality. ConclusionsThe present study is the first to measure personal light exposures in office workers using a calibrated device that measures circadian-effective light and relate those light measures to mood, stress, and sleep. The study's results underscore the importance of daytime light exposures for sleep health.

Atomic mutagenesis in ion channels with engineered stoichiometry.

C-type inactivation of potassium channels fine-tunes the electrical signaling in excitable cells through an internal timing mechanism that is mediated by a hydrogen bond network in the channels' selectively filter. Previously, we used nonsense suppression to highlight the role of the conserved Trp434-Asp447 indole hydrogen bond in Shaker potassium channels with a non-hydrogen bonding homologue of tryptophan, Ind (Pless et al., 2013). Here, molecular dynamics simulations indicate that the Trp434Ind hydrogen bonding partner, Asp447, unexpectedly 'flips out' towards the extracellular environment, allowing water to penetrate the space behind the selectivity filter while simultaneously reducing the local negative electrostatic charge. Additionally, a protein engineering approach is presented whereby split intein sequences are flanked by endoplasmic reticulum retention/retrieval motifs (ERret) are incorporated into the N- or C- termini of Shaker monomers or within sodium channels two-domain fragments. This system enabled stoichiometric control of Shaker monomers and the encoding of multiple amino acids within a channel tetramer.

The intervertebral disc contains intrinsic circadian clocks that are regulated by age and cytokines and linked to degeneration

ObjectivesThe circadian clocks are internal timing mechanisms that drive ∼24-hour rhythms in a tissue-specific manner. Many aspects of the physiology of the intervertebral disc (IVD) show clear diurnal rhythms. However,...

Engineering Subunit and Nonsense Suppression Stoichiometry in Potassium Channels

Multi-subunit membrane proteins employ chemically diverse inter- and intramolecular contacts to regulate their function. Potassium channel slow inactivation relies on a hydrogen bond network around the selectivity filter which supports an internal timing mechanism to control the transition between conducting and non-conducting conformations. Previously we used targeted replacement of W434 with the isosteric non-canonical amino acid 2-amino-3-indol-1-yl-propionic acid (Ind) to highlight the importance of the indole H-bond of this highly conserved Trp residue. However, these experiments were unable to nuance the specific contributions of individual channel subunits to channel inactivation. We therefore designed an engineered protein approach whereby complementary intein sequences are incorporated into the N- or C- termini of Shaker monomers, respectively, flanked by previously identified endoplasmic reticulum (ER) retention signals. The data shows that functional channels composed of monomeric ER-intein subunits are restricted from the surface membrane. However, co-expression of complementary ER-intein monomers results in robust expression of functional K+ channels through intein ligation and excision of both the ER retention signals and intein sequences. This technique was used to express Shaker channels with two W434Ind monomers within a single tetramer, producing an intermediate inactivation rate, consistent with the breakage of multiple H-bonds required for full inactivation. In addition, the fidelity of the stoichiometric assembly was assayed by TEA block of channels with zero, two or four T449F mutations. The development of this approach allows for regulation of subunit stoichiometry in multimeric complexes and advances the use of nonsense suppression by demonstrating a solution to incorporate multiple non-canonical amino acids into a single peptide and multimeric complexes. Specifically, the reduction of overall protein expression that is normally compounded at the second suppression site is effectively abrogated because two transcripts are suppressed independently then ligated as proteins.

Phototropins do not alter accumulation of evening-phased circadian transcripts under blue light

ABSTRACTThe circadian system induces rhythmic variation in a suite of biochemical and physiological processes that serve to optimise plant growth in diel cycles. To be of greatest utility, these rhythmic behaviors are coordinated with regular environmental changes such as the rising and setting of the sun. Photoreceptors, along with metabolites produced during photosynthesis, act to synchronise the internal timing mechanism with lighting cues. We have recently shown that phototropins help maintain robust rhythms of photosynthetic operating efficiency (ϕPSII or Fq′/Fm′) under blue light, although rhythmic accumulation of morning-phased circadian transcripts in the nucleus was unaffected. Here we report that evening-phased nuclear clock transcripts were also unaffected. We also observe that rhythms of nuclear clock transcript accumulation are maintained in phototropin mutant plants under a fluctuating lighting regime that induced a loss of Fq′/Fm′ rhythms.

Time-order error and scalar variance in a computational model of human timing: simulations and predictions

This work introduces a computational model of human temporal discrimination mechanism – the Clock-Counter Timing Network. It is an artificial neural network implementation of a timing mechanism based on the informational architecture of the popular Scalar Timing Model. The model has been simulated in a virtual environment enabling computational experiments which imitate a temporal discrimination task – the two-alternative forced choice task. The influence of key parameters of the model (including the internal pacemaker speed and the variability of memory translation) on the network accuracy and the time-order error phenomenon has been evaluated. The results of simulations reveal how activities of different modules contribute to the overall performance of the model. While the number of significant effects is quite large, the article focuses on the relevant observations concerning the influence of the pacemaker speed and the scalar source of variance on the measured indicators of network performance. The results of performed experiments demonstrate consequences of the fundamental assumptions of the clock-counter model for the results in a temporal discrimination task. The results can be compared and verified in empirical experiments with human participants, especially when the modes of activity of the internal timing mechanism are changed because of some external conditions, or are impaired due to some kind of a neural degradation process.

Beta oscillations, timing, and stuttering.

Beta oscillations, timing, and stuttering.

Visuotactile Temporal Recalibration Transfers Across Different Locations.

Following prolonged exposure to audiovisual asynchrony, an observer's point of subjective simultaneity (PSS) shifts in the direction of the leading modality. It has been debated whether other sensory pairings, such as vision and touch, lead to a similar temporal recalibration, and if so, whether the internal timing mechanism underlying lag visuotactile adaptation is centralised or distributed. To address these questions, we adapted observers to vision- and tactile-leading visuotactile asynchrony on either their left or right hand side in different blocks. In one test condition, participants performed a simultaneity judgment on the adapted side (unilateral) and in another they performed a simultaneity judgment on the non-adapted side (contralateral). In a third condition, participants adapted concurrently to equal and opposite asynchronies on each side and were tested randomly on either hand (bilateral opposed). Results from the first two conditions show that observers recalibrate to visuotactile asynchronies, and that the recalibration transfers to the non-adapted side. These findings suggest a centralised recalibration mechanism not linked to the adapted side and predict no recalibration for the bilateral opposed condition, assuming the adapted effects were equal on each side. This was confirmed in the group of participants that adapted to vision- and tactile-leading asynchrony on the right and left hand side, respectively. However, the other group (vision-leading on the left and tactile-leading on the right) did show a recalibration effect, suggesting a distributed mechanism. We discuss these findings in terms of a hybrid model that assumes the co-existence of a centralised and distributed timing mechanism.