Insulin/IGF-1 Drives PERIOD Synthesis to Entrain Circadian Rhythms with Feeding Time.

In mammals, endogenous circadian clocks sense and respond to daily feeding and lighting cues, adjusting internal ∼24 h rhythms to resonate with, and anticipate, external cycles of day and night. The mechanism underlying circadian entrainment to feeding time is critical for understanding why mistimed feeding, as occurs during shift work, disrupts circadian physiology, a state that is associated with increased incidence of chronic diseases such as type 2 (T2) diabetes. We show that feeding-regulated hormones insulin and insulin-like growth factor 1 (IGF-1) reset circadian clocks in vivo and in vitro by induction of PERIOD proteins, and mistimed insulin signaling disrupts circadian organization of mouse behavior and clock gene expression. Insulin and IGF-1 receptor signaling is sufficient to determine essential circadian parameters, principally via increased PERIOD protein synthesis. This requires coincident mechanistic target of rapamycin (mTOR) activation, increased phosphoinositide signaling, and microRNA downregulation. Besides its well-known homeostatic functions, we propose insulin and IGF-1 are primary signals of feeding time to cellular clocks throughout the body.

Modulation of Phase Shift between Wnt and Notch Signaling Oscillations Controls Mesoderm Segmentation.

How signaling dynamics encode information is a central question in biology. During vertebrate development, dynamic Notch signaling oscillations control segmentation of the presomitic mesoderm (PSM). In mouse embryos, this molecular clock comprises signaling oscillations of several pathways, i.e., Notch, Wnt, and FGF signaling. Here, we directly address the role of the relative timing between Wnt and Notch signaling oscillations during PSM patterning. To this end, we developed a new experimental strategy using microfluidics-based entrainment that enables specific control of the rhythm of segmentation clock oscillations. Using this approach, we find that Wnt and Notch signaling are coupled at the level of their oscillation dynamics. Furthermore, we provide functional evidence that the oscillation phase shift between Wnt and Notch signaling is critical for PSM segmentation. Our work hence reveals that dynamic signaling, i.e., the relative timing between oscillatory signals, encodes essential information during multicellular development.

Dynamics and timekeeping in biological systems.

This article introduces three reviews on the theme of circadian rhythms.

Long-term core-mantle interaction explains W-He isotope heterogeneities.

The isotopic characteristics of ocean island basalts have long been used to infer the nature of their source and the long-term evolution of the Earth's mantle. Anticorrelation between tungsten and helium isotopic signatures is a particularly puzzling feature in those basalts, which no single process appears to explain. Traditionally, the high 3He/4He signature has been attributed to an undegassed reservoir in the deep mantle. Additional processes needed to obtain low 182W/184W often entail unobserved ancillary geochemical effects. It has been suggested, however, that the core feeds the lower mantle with primordial helium, obviating the need for an undegassed mantle reservoir. Independently, the tungsten-rich core has been suggested to impart the plume source with anomalous tungsten isotope signatures. We advance the idea that isotopic diffusion may simultaneously transport both tungsten and helium across the core-mantle boundary, with the striking implication that diffusion can naturally account for the observed isotopic trend. By modeling the long-term isotopic evolution of mantle domains, we demonstrate that this mechanism can account for more than sufficient isotopic ratios in plume-source material, which, after dynamical transport to the Earth's surface, are consistent with the present-day mantle W-He isotopic heterogeneities. No undegassed mantle reservoir is required, bearing significance on early Earth conditions such as the extent of magma oceans.

Tuning in to real-time social interactions in macaques.

Movement synchronization between individuals has been implicated in reinforcing their cohesion. How might such interindividual motor entrainment be controlled by the social brain? The answer remains elusive owing largely to the lack of suitable animal models in which direct neural recordings are available. Here, we show that macaque monkeys exhibit social motor entrainment without human prompting. We found that repetitive arm movements for horizontal bar sliding were phase coherent between two monkeys. The nature of motor entrainment was specific to animal pairs, consistent across days, dependent on visual inputs, and affected by social hierarchy. Notably, the entrainment was diminished when paired with prerecorded movies of a monkey making the same movements or bar motion alone. These findings demonstrate that motor entrainment is facilitated by real-time social exchanges, providing a behavioral platform to study the neural basis of potentially evolutionarily conserved mechanisms that support group cohesion.

Cloud microphysical response to entrainment and mixing is locally inhomogeneous and globally homogeneous: Evidence from the lab.

Entrainment of dry air into clouds strongly influences cloud optical and precipitation properties and the response of clouds to aerosol perturbations. The response of cloud droplet size distributions to entrainment-mixing is examined in the Pi convection-cloud chamber that creates a turbulent, steady-state cloud. The experiments are conducted by injecting dry air with temperature (Te) and flow rate (Qe) through a flange in the top boundary, into the otherwise well-mixed cloud, to mimic the entrainment-mixing process. Due to the large-scale circulation, the downwind region is directly affected by entrained dry air, whereas the upwind region is representative of the background conditions. Droplet concentration (Cn) and liquid water content (L) decrease in the downwind region, but the difference in the mean diameter of droplets (Dm) is small. The shape of cloud droplet size distributions relative to the injection point is unchanged, to within statistical uncertainty, resulting in a signature of inhomogeneous mixing, as expected for droplet evaporation times small compared to mixing time scales. As Te and Qe of entrained air increase, however, Cn, L, and Dm of the whole cloud system decrease, resulting in a signature of homogeneous mixing. The apparent contradiction is understood as the cloud microphysical responses to entrainment and mixing differing on local and global scales: locally inhomogeneous and globally homogeneous. This implies that global versus local sampling of clouds can lead to seemingly contradictory results for mixing, which informs the long-standing debate about the microphysical response to entrainment and the parameterization of this process for coarse-resolution models.

Speech Prosody Serves Temporal Prediction of Language via Contextual Entrainment.

Temporal prediction assists language comprehension. In a series of recent behavioral studies, we have shown that listeners specifically employ rhythmic modulations of prosody to estimate the duration of upcoming sentences, thereby speeding up comprehension. In the current human magnetoencephalography (MEG) study on participants of either sex, we show that the human brain achieves this function through a mechanism termed entrainment. Through entrainment, electrophysiological brain activity maintains and continues contextual rhythms beyond their offset. Our experiment combined exposure to repetitive prosodic contours with the subsequent presentation of visual sentences that either matched or mismatched the duration of the preceding contour. During exposure to prosodic contours, we observed MEG coherence with the contours, which was source-localized to right-hemispheric auditory areas. During the processing of the visual targets, activity at the frequency of the preceding contour was still detectable in the MEG; yet sources shifted to the (left) frontal cortex, in line with a functional inheritance of the rhythmic acoustic context for prediction. Strikingly, when the target sentence was shorter than expected from the preceding contour, an omission response appeared in the evoked potential record. We conclude that prosodic entrainment is a functional mechanism of temporal prediction in language comprehension. In general, acoustic rhythms appear to endow language for employing the brain's electrophysiological mechanisms of temporal prediction.

High-frequency transcranial alternating current stimulation matching individual frequency of somatosensory evoked high-frequency oscillations can modulate the somatosensory system through thalamocortical pathway.

tACS (transcranial alternating current stimulation) is a technique for modulating brain activity through electrical current. Its effects depend on cortical entrainment, which is most effective when transcranial alternating current stimulation matches the brain's natural rhythm. High-frequency oscillations produced by external stimuli are useful for studying the somatosensory pathway. Our study aims to explore transcranial alternating current stimulation's impact on the somatosensory system when synchronized with individual high-frequency oscillation frequencies. We conducted a randomized, sham-controlled study with 14 healthy participants. The study had three phases: Individualized transcranial alternating current stimulation (matching the individual's high-frequency oscillation rhythm), Standard transcranial alternating current stimulation (600 Hz), and sham stimulation. We measured early and late HFO components after median nerve electrical stimulation at three time points: before (T0), immediately after (T1), and 10 min after transcranial alternating current stimulation (T2). Compared to Sham and Standard stimulation Individualized transcranial alternating current stimulation significantly enhanced high-frequency oscillations, especially the early component, immediately after stimulation and for at least 15 min. No other effects were observed for other high-frequency oscillation measures. In summary, our study provides initial evidence that transcranial alternating current stimulation synchronized with an individual's high-frequency oscillation frequency can precisely and time-specifically modulate thalamocortical activity. These insights may pave the way for innovative, personalized neuromodulation methods for the somatosensory system.

Neural consequences of binaural beat stimulation on auditory sentence comprehension: an EEG study.

A growing literature has shown that binaural beat (BB)-generated by dichotic presentation of slightly mismatched pure tones-improves cognition. We recently found that BB stimulation of either beta (18 Hz) or gamma (40 Hz) frequencies enhanced auditory sentence comprehension. Here, we used electroencephalography (EEG) to characterize neural oscillations pertaining to the enhanced linguistic operations following BB stimulation. Sixty healthy young adults were randomly assigned to one of three listening groups: 18-Hz BB, 40-Hz BB, or pure-tone baseline, all embedded in music. After listening to the sound for 10 min (stimulation phase), participants underwent an auditory sentence comprehension task involving spoken sentences that contained either an object or subject relative clause (task phase). During the stimulation phase, 18-Hz BB yielded increased EEG power in a beta frequency range, while 40-Hz BB did not. During the task phase, only the 18-Hz BB resulted in significantly higher accuracy and faster response times compared with the baseline, especially on syntactically more complex object-relative sentences. The behavioral improvement by 18-Hz BB was accompanied by attenuated beta power difference between object- and subject-relative sentences. Altogether, our findings demonstrate beta oscillations as a neural correlate of improved syntactic operation following BB stimulation.

An Unstable Singularity Underlies Stochastic Phasing of the Circadian Clock in Individual Cyanobacterial Cells.

The endogenous circadian clock synchronizes with environmental time by appropriately resetting its phase in response to external cues. Of note, some resetting stimuli induce attenuated oscillations of clock output, which has been observed at the population-level in several organisms and in studies of individual humans. To investigate what is happening in individual cellular clocks, we studied the unicellular cyanobacterium S. elongatus. By measuring its phase-resetting responses to temperature changes, we found that population-level arrhythmicity occurs when certain perturbations cause stochastic phases of oscillations in individual cells. Combining modeling with experiments, we related stochastic phasing to the dynamical structure of the cyanobacterial clock as an oscillator and explored the physiological relevance of the oscillator structure for accurately timed rhythmicity in changing environmental conditions. Our findings and approach can be applied to other biological oscillators.

Music of infant-directed singing entrains infants' social visual behavior.

Infant-directed singing is a culturally universal musical phenomenon known to promote the bonding of infants and caregivers. Entrainment is a widely observed physical phenomenon by which diverse physical systems adjust rhythmic activity through interaction. Here we show that the simple act of infant-directed singing entrains infant social visual behavior on subsecond timescales, increasing infants' looking to the eyes of a singing caregiver: as early as 2 months of age, and doubling in strength by 6 months, infants synchronize their eye-looking to the rhythm of infant-directed singing. Rhythmic entrainment also structures caregivers' own cueing, enhancing their visual display of social-communicative content: caregivers increase wide-eyed positive affect, reduce neutral facial affect, reduce eye motion, and reduce blinking, all in time with the rhythm of their singing and aligned in time with moments when infants increase their eye-looking. In addition, if the rhythm of infant-directed singing is experimentally disrupted-reducing its predictability-then infants' time-locked eye-looking is also disrupted. These results reveal generic processes of entrainment as a fundamental coupling mechanism by which the rhythm of infant-directed singing attunes infants to precisely timed social-communicative content and supports social learning and development.

The duper mutation reveals previously unsuspected functions of Cryptochrome 1 in circadian entrainment and heart disease.

The Cryptochrome 1 (Cry1)-deficient duper mutant hamster has a short free-running period in constant darkness (τDD) and shows large phase shifts in response to brief light pulses. We tested whether this measure of the lability of the circadian phase is a general characteristic of Cry1-null animals and whether it indicates resistance to jet lag. Upon advance of the light:dark (LD) cycle, both duper hamsters and Cry1-/- mice re-entrained locomotor rhythms three times as fast as wild types. However, accelerated re-entrainment was dissociated from the amplified phase-response curve (PRC): unlike duper hamsters, Cry1-/- mice show no amplification of the phase response to 15' light pulses. Neither the amplified acute shifts nor the increased rate of re-entrainment in duper mutants is due to acceleration of the circadian clock: when mutants drank heavy water to lengthen the period, these aspects of the phenotype persisted. In light of the health consequences of circadian misalignment, we examined effects of duper and phase shifts on a hamster model of heart disease previously shown to be aggravated by repeated phase shifts. The mutation shortened the lifespan of cardiomyopathic hamsters relative to wild types, but this effect was eliminated when mutants experienced 8-h phase shifts every second week, to which they rapidly re-entrained. Our results reveal previously unsuspected roles of Cry1 in phase shifting and longevity in the face of heart disease. The duper mutant offers new opportunities to understand the basis of circadian disruption and jet lag.

Rhythmic Entrainment Echoes in Auditory Perception.

Rhythmic entrainment echoes-rhythmic brain responses that outlast rhythmic stimulation-can demonstrate endogenous neural oscillations entrained by the stimulus rhythm. Here, we tested for such echoes in auditory perception. Participants detected a pure tone target, presented at a variable delay after another pure tone that was rhythmically modulated in amplitude. In four experiments involving 154 human (female and male) participants, we tested (1) which stimulus rate produces the strongest entrainment echo and, inspired by the tonotopical organization of the auditory system and findings in nonhuman primates, (2) whether these are organized according to sound frequency. We found the strongest entrainment echoes after 6 and 8 Hz stimulation, respectively. The best moments for target detection (in phase or antiphase with the preceding rhythm) depended on whether sound frequencies of entraining and target stimuli matched, which is in line with a tonotopical organization. However, for the same experimental condition, best moments were not always consistent across experiments. We provide a speculative explanation for these differences that relies on the notion that neural entrainment and repetition-related adaptation might exercise competing opposite influences on perception. Together, we find rhythmic echoes in auditory perception that seem more complex than those predicted from initial theories of neural entrainment.SIGNIFICANCE STATEMENT Rhythmic entrainment echoes are rhythmic brain responses that are produced by a rhythmic stimulus and persist after its offset. These echoes play an important role for the identification of endogenous brain oscillations, entrained by rhythmic stimulation, and give us insights into whether and how participants predict the timing of events. In four independent experiments involving >150 participants, we examined entrainment echoes in auditory perception. We found that entrainment echoes have a preferred rate (between 6 and 8 Hz) and seem to follow the tonotopic organization of the auditory system. Although speculative, we also found evidence that several, potentially competing processes might interact to produce such echoes, a notion that might need to be considered for future experimental design.

On the Functional Role of Gamma Synchronization in the Retinogeniculate System of the Cat.

Fast gamma oscillations, generated within the retina, and transmitted to the cortex via the lateral geniculate nucleus (LGN), are thought to carry information about stimulus size and continuity. This hypothesis relies mainly on studies conducted under anesthesia and the extent to which it holds under more naturalistic conditions remains unclear. Using multielectrode recordings of spiking activity in the retina and the LGN of both male and female cats, we show that visually driven gamma oscillations are absent for awake states and are highly dependent on halothane (or isoflurane). Under ketamine, responses were nonoscillatory, as in the awake condition. Response entrainment to the monitor refresh was commonly observed up to 120 Hz and was superseded by the gamma oscillatory responses induced by halothane. Given that retinal gamma oscillations are contingent on halothane anesthesia and absent in the awake cat, such oscillations should be considered artifactual, thus playing no functional role in vision.SIGNIFICANCE STATEMENT Gamma rhythms have been proposed to be a robust encoding mechanism critical for visual processing. In the retinogeniculate system of the cat, many studies have shown gamma oscillations associated with responses to static stimuli. Here, we extend these observations to dynamic stimuli. An unexpected finding was that retinal gamma responses strongly depend on halothane concentration levels and are absent in the awake cat. These results weaken the notion that gamma in the retina is relevant for vision. Notably, retinal gamma shares many of the properties of cortical gamma. In this respect, oscillations induced by halothane in the retina may serve as a valuable preparation, although artificial, for studying oscillatory dynamics.

Rhythm in the Premature Neonate Brain: Very Early Processing of Auditory Beat and Meter.

The ability to extract rhythmic structure is important for the development of language, music, and social communication. Although previous studies show infants' brains entrain to the periodicities of auditory rhythms and even different metrical interpretations (e.g., groups of two vs three beats) of ambiguous rhythms, whether the premature brain tracks beat and meter frequencies has not been explored previously. We used high-resolution electroencephalography while premature infants (n = 19, 5 male; mean age, 32 ± 2.59 weeks gestational age) heard two auditory rhythms in the incubators. We observed selective enhancement of the neural response at both beat- and meter-related frequencies. Further, neural oscillations at the beat and duple (groups of 2) meter were phase aligned with the envelope of the auditory rhythmic stimuli. Comparing the relative power at beat and meter frequencies across stimuli and frequency revealed evidence for selective enhancement of duple meter. This suggests that even at this early stage of development, neural mechanisms for processing auditory rhythms beyond simple sensory coding are present. Our results add to a few previous neuroimaging studies demonstrating discriminative auditory abilities of premature neural networks. Specifically, our results demonstrate the early capacities of the immature neural circuits and networks to code both simple beat and beat grouping (i.e., hierarchical meter) regularities of auditory sequences. Considering the importance of rhythm processing for acquiring language and music, our findings indicate that even before birth, the premature brain is already learning this important aspect of the auditory world in a sophisticated and abstract way.SIGNIFICANCE STATEMENT Processing auditory rhythm is of great neurodevelopmental importance. In an electroencephalography experiment in premature newborns, we found converging evidence that when presented with auditory rhythms, the premature brain encodes multiple periodicities corresponding to beat and beat grouping (meter) frequencies, and even selectively enhances the neural response to meter compared with beat, as in human adults. We also found that the phase of low-frequency neural oscillations aligns to the envelope of the auditory rhythms and that this phenomenon becomes less precise at lower frequencies. These findings demonstrate the initial capacities of the developing brain to code auditory rhythm and the importance of special care to the auditory environment of this vulnerable population during a highly dynamic period of neural development.

Speech perception difficulty modulates theta-band encoding of articulatory synergies.

The human brain tracks available speech acoustics and extrapolates missing information such as the speaker's articulatory patterns. However, the extent to which articulatory reconstruction supports speech perception remains unclear. This study explores the relationship between articulatory reconstruction and task difficulty. Participants listened to sentences and performed a speech-rhyming task. Real kinematic data of the speaker's vocal tract were recorded via electromagnetic articulography (EMA) and aligned to corresponding acoustic outputs. We extracted articulatory synergies from the EMA data with principal component analysis (PCA) and employed partial information decomposition (PID) to separate the electroencephalographic (EEG) encoding of acoustic and articulatory features into unique, redundant, and synergistic atoms of information. We median-split sentences into easy (ES) and hard (HS) based on participants' performance and found that greater task difficulty involved greater encoding of unique articulatory information in the theta band. We conclude that fine-grained articulatory reconstruction plays a complementary role in the encoding of speech acoustics, lending further support to the claim that motor processes support speech perception.NEW & NOTEWORTHY Top-down processes originating from the motor system contribute to speech perception through the reconstruction of the speaker's articulatory movement. This study investigates the role of such articulatory simulation under variable task difficulty. We show that more challenging listening tasks lead to increased encoding of articulatory kinematics in the theta band and suggest that, in such situations, fine-grained articulatory reconstruction complements acoustic encoding.

Neural tracking of continuous acoustics: properties, speech-specificity and open questions.

Human speech is a particularly relevant acoustic stimulus for our species, due to its role of information transmission during communication. Speech is inherently a dynamic signal, and a recent line of research focused on neural activity following the temporal structure of speech. We review findings that characterise neural dynamics in the processing of continuous acoustics and that allow us to compare these dynamics with temporal aspects in human speech. We highlight properties and constraints that both neural and speech dynamics have, suggesting that auditory neural systems are optimised to process human speech. We then discuss the speech-specificity of neural dynamics and their potential mechanistic origins and summarise open questions in the field.

Steven A. Brown and the synchronization of circadian rhythms by body temperature cycles.

The mammalian circadian timing system has a hierarchical architecture, with a central pacemaker located in the brain's suprachiasmatic nucleus orchestrating rhythms in behaviour and physiology. In cooperation with environmental cycles, it synchronizes the phases of peripheral oscillators operating in most cells of the body. Even cells kept in tissue culture harbour self-sustained and cell-autonomous circadian clocks that keep ticking throughout their lifespan. The master pacemaker in the suprachiasmatic nucleus is synchronized primarily by light-dark cycles, whereas peripheral oscillators are phase entrained by a multitude of systemic signalling pathways. These include pathways depending on feeding-fasting cycles, cellular actin polymerization dynamics, endocrine rhythms and, surprisingly, body temperature oscillations. Using tissue culture and murine models, Steve Brown was the first one to demonstrate that shallow rhythms of mammalian body temperature are timing cues (zeitgebers) for peripheral circadian clocks.

Optimal gamma-band entrainment of visual cortex.

Visual entrainment is a powerful and widely used research tool to study visual information processing in the brain. While many entrainment studies have focused on frequencies around 14-16 Hz, there is renewed interest in understanding visual entrainment at higher frequencies (e.g., gamma-band entrainment). Notably, recent groundbreaking studies have demonstrated that gamma-band visual entrainment at 40 Hz may have therapeutic effects in the context of Alzheimer's disease (AD) by stimulating specific neural ensembles, which utilize GABAergic signaling. Despite such promising findings, few studies have investigated the optimal parameters for gamma-band visual entrainment. Herein, we examined whether visual stimulation at 32, 40, or 48 Hz produces optimal visual entrainment responses using high-density magnetoencephalography (MEG). Our results indicated strong entrainment responses localizing to the primary visual cortex in each condition. Entrainment responses were stronger for 32 and 40 Hz relative to 48 Hz, indicating more robust synchronization of neural ensembles at these lower gamma-band frequencies. In addition, 32 and 40 Hz entrainment responses showed typical patterns of habituation across trials, but this effect was absent for 48 Hz. Finally, connectivity between visual cortex and parietal and prefrontal cortices tended to be strongest for 40 relative to 32 and 48 Hz entrainment. These results suggest that neural ensembles in the visual cortex may resonate at around 32 and 40 Hz and thus entrain more readily to photic stimulation at these frequencies. Emerging AD therapies, which have focused on 40 Hz entrainment to date, may be more effective at lower relative to higher gamma frequencies, although additional work in clinical populations is needed to confirm these findings. PRACTITIONER POINTS: Gamma-band visual entrainment has emerged as a therapeutic approach for eliminating amyloid in Alzheimer's disease, but its optimal parameters are unknown. We found stronger entrainment at 32 and 40 Hz compared to 48 Hz, suggesting neural ensembles prefer to resonate around these relatively lower gamma-band frequencies. These findings may inform the development and refinement of innovative AD therapies and the study of GABAergic visual cortical functions.

The circadian clock and thermal regulation in plants: novel insights into the role of positive circadian clock regulators in temperature responses.

The impact of rising global temperatures on crop yields is a serious concern, and the development of heat-resistant crop varieties is crucial for mitigating the effects of climate change on agriculture. To achieve this, a better understanding of the molecular basis of the thermal responses of plants is necessary. The circadian clock plays a central role in modulating plant biology in synchrony with environmental changes, including temperature fluctuations. Recent studies have uncovered the role of transcriptional activators of the core circadian network in plant temperature responses. This expert view highlights key novel findings regarding the role of the RVE and LNK gene families in controlling gene expression patterns and plant growth under different temperature conditions, ranging from regular diurnal oscillations to extreme stress temperatures. These findings reinforce the essential role of the circadian clock in plant adaptation to changing temperatures and provide a basis for future studies on crop improvement.