Optogenetic perturbation and bioluminescence imaging to analyze cell-to-cell transfer of oscillatory information.

Cells communicate with each other to coordinate their gene activities at the population level through signaling pathways. It has been shown that many gene activities are oscillatory and that the frequency and phase of oscillatory gene expression encode various types of information. However, whether or how such oscillatory information is transmitted from cell to cell remains unknown. Here, we developed an integrated approach that combines optogenetic perturbations and single-cell bioluminescence imaging to visualize and reconstitute synchronized oscillatory gene expression in signal-sending and signal-receiving processes. We found that intracellular and intercellular periodic inputs of Notch signaling entrain intrinsic oscillations by frequency tuning and phase shifting at the single-cell level. In this way, the oscillation dynamics are transmitted through Notch signaling, thereby synchronizing the population of oscillators. Thus, this approach enabled us to control and monitor dynamic cell-to-cell transfer of oscillatory information to coordinate gene expression patterns at the population level.

Pairing with Enriched Sound Exposure Restores Auditory Processing Degraded by an Antidepressant.

Antidepressants, while effective in treating depression and anxiety disorders, also induce deficits in sensory (particularly auditory) processing, which in turn may exacerbate psychiatric symptoms. How antidepressants cause auditory signature deficits remains largely unknown. Here, we found that fluoxetine-treated adult female rats were significantly less accurate when performing a tone-frequency discrimination task compared with age-matched control rats. Their cortical neurons also responded less selectively to sound frequencies. The degraded behavioral and cortical processing was accompanied by decreased cortical perineuronal nets, particularly those wrapped around parvalbumin-expressing inhibitory interneurons. Furthermore, fluoxetine induced critical period-like plasticity in their already mature auditory cortices; therefore, a brief rearing of these drug-treated rats under an enriched acoustic environment renormalized auditory processing degraded by fluoxetine. The altered cortical expression of perineuronal nets was also reversed as a result of enriched sound exposure. These findings suggest that the adverse effects of antidepressants on auditory processing, possibly because of a reduction in intracortical inhibition, can be substantially alleviated by simply pairing drug treatment with passive, enriched sound exposure. They have important implications for understanding the neurobiological basis of antidepressant effects on hearing and for designing novel pharmacological treatment strategies for psychiatric disorders.SIGNIFICANCE STATEMENT Clinical experience suggests that antidepressants adversely affect sensory (particularly auditory) processing, which can exacerbate patients' psychiatric symptoms. Here, we show that the antidepressant fluoxetine reduces cortical inhibition in adult rats, leading to degraded behavioral and cortical spectral processing of sound. Importantly, fluoxetine induces a critical period-like state of plasticity in the mature cortex; therefore, a brief rearing under an enriched acoustic environment is sufficient to reverse the changes in auditory processing caused by the administration of fluoxetine. These results provide a putative neurobiological basis for the effects of antidepressants on hearing and indicate that antidepressant treatment combined with enriched sensory experiences could optimize clinical outcomes.

Selective attention sharpens population receptive fields in human auditory cortex.

Selective attention enables the preferential processing of relevant stimulus aspects. Invasive animal studies have shown that attending a sound feature rapidly modifies neuronal tuning throughout the auditory cortex. Human neuroimaging studies have reported enhanced auditory cortical responses with selective attention. To date, it remains unclear how the results obtained with functional magnetic resonance imaging (fMRI) in humans relate to the electrophysiological findings in animal models. Here we aim to narrow the gap between animal and human research by combining a selective attention task similar in design to those used in animal electrophysiology with high spatial resolution ultra-high field fMRI at 7 Tesla. Specifically, human participants perform a detection task, whereas the probability of target occurrence varies with sound frequency. Contrary to previous fMRI studies, we show that selective attention resulted in population receptive field sharpening, and consequently reduced responses, at the attended sound frequencies. The difference between our results to those of previous fMRI studies supports the notion that the influence of selective attention on auditory cortex is diverse and may depend on context, stimulus, and task.

A stable sensory map emerges from a dynamic equilibrium of neurons with unstable tuning properties.

Recent long-term measurements of neuronal activity have revealed that, despite stability in large-scale topographic maps, the tuning properties of individual cortical neurons can undergo substantial reformatting over days. To shed light on this apparent contradiction, we captured the sound response dynamics of auditory cortical neurons using repeated 2-photon calcium imaging in awake mice. We measured sound-evoked responses to a set of pure tone and complex sound stimuli in more than 20,000 auditory cortex neurons over several days. We found that a substantial fraction of neurons dropped in and out of the population response. We modeled these dynamics as a simple discrete-time Markov chain, capturing the continuous changes in responsiveness observed during stable behavioral and environmental conditions. Although only a minority of neurons were driven by the sound stimuli at a given time point, the model predicts that most cells would at least transiently become responsive within 100 days. We observe that, despite single-neuron volatility, the population-level representation of sound frequency was stably maintained, demonstrating the dynamic equilibrium underlying the tonotopic map. Our results show that sensory maps are maintained by shifting subpopulations of neurons "sharing" the job of creating a sensory representation.

An ADPLL-Based GFSK Modulator with Two-Point Modulation for IoT Applications.

To establish ubiquitous and energy-efficient wireless sensor networks (WSNs), short-range Internet of Things (IoT) devices require Bluetooth low energy (BLE) technology, which functions at 2.4 GHz. This study presents a novel approach as follows: a fully integrated all-digital phase-locked loop (ADPLL)-based Gaussian frequency shift keying (GFSK) modulator incorporating two-point modulation (TPM). The modulator aims to enhance the efficiency of BLE communication in these networks. The design includes a time-to-digital converter (TDC) with the following three key features to improve linearity and time resolution: fast settling time, low dropout regulators (LDOs) that adapt to process, voltage, and temperature (PVT) variations, and interpolation assisted by an analog-to-digital converter (ADC). It features a digital controlled oscillator (DCO) with two key enhancements as follows: ΔΣ modulator dithering and hierarchical capacitive banks, which expand the frequency tuning range and improve linearity, and an integrated, fast-converging least-mean-square (LMS) algorithm for DCO gain calibration, which ensures compliance with BLE 5.0 stable modulation index (SMI) requirements. Implemented in a 28 nm CMOS process, occupying an active area of 0.33 mm2, the modulator demonstrates a wide frequency tuning range of from 2.21 to 2.58 GHz, in-band phase noise of -102.1 dBc/Hz, and FSK error of 1.42% while consuming 1.6 mW.

Dynamics and Mechanisms of Contrast-Dependent Modulation of Spatial-Frequency Tuning in the Early Visual Cortex.

The spatial-frequency (SF) tuning of neurons in the early visual cortex is adjusted for stimulus contrast. As the contrast increases, SF tuning is modulated so that the transmission of fine features is facilitated. A variety of mechanisms are involved in shaping SF tunings, but those responsible for the contrast-dependent modulations are unclear. To address this, we measured the time course of SF tunings of area 17 neurons in male cats under different contrasts with a reverse correlation. After response onset, the optimal SF continuously shifted to a higher SF over time, with a larger shift for higher contrast. At high contrast, whereas neurons with a large shift of optimal SF exhibited a large bandwidth decrease, those with a negligible shift increased the bandwidth over time. Between these two extremes, the degree of SF shift and bandwidth change continuously varied. At low contrast, bandwidth generally decreased over time. These dynamic effects enhanced the processing of high-frequency range under a high-contrast condition and allowed time-average SF tuning curves to show contrast-dependent modulation, like that of steady-state SF tuning curves reported previously. Combinations of two mechanisms, one that decreases bandwidth and shifts optimal SF, and another that increases bandwidth without shifting optimal SF, would explain the full range of SF tuning dynamics. Our results indicate that one of the essential roles of tuning dynamics of area 17 neurons, which have been observed for various visual features, is to adjust tunings depending on contrast.SIGNIFICANCE STATEMENT The spatial scales of features transmitted by cortical neurons are adjusted depending on stimulus contrast. However, the underlying mechanism is not fully understood. We measured the time course of spatial frequency tunings of cat area 17 neurons under different contrast conditions and observed a variety of dynamic effects that contributed to spatial-scale adjustment, allowing neurons to adjust their spatial frequency tuning range depending on contrast. Our results suggest that one of the essential roles of tuning dynamics of area 17 neurons, which have been observed for various visual features, is to adjust tunings depending on contrast.

Enhancement of temperature-modulated NbO2-based relaxation oscillator via interfacial and bulk treatments.

This work demonstrates oscillation frequency modulation in a NbO2-based relaxation oscillator device, in which the oscillation frequency increases with operating temperature and source voltage, and decreases with load resistance. An annealing-induced oxygen diffusion at 373 K was carried out to optimize the stoichiometry of the bulk NbO2to achieve consistent oscillation frequency shift with device temperature. The device exhibits stable self-sustained oscillation in which the frequency can be modulated between 2 and 33 MHz, and a wider operating voltage range can be obtained. An additional surface treatment step was employed during fabrication to reduce the surface roughness of the bottom electrode and to remove surface contaminants that affect the interfacial properties of the device. The device frequency tunability coupled with high oscillating frequency and high endurance capability of more than 1.5 × 108cycles indicates that the Pt/NbO2/Pt device is particularly suitable for applications in an oscillatory neural network.

Frequency Scaling, Elastic Transition, and Broad-Range Frequency Tuning in WSe2 Nanomechanical Resonators.

Nanomechanical resonators based on atomic layers of tungsten diselenide (WSe2) offer intriguing prospects for enabling novel sensing and signal processing functions. The frequency scaling law of such resonant devices is critical for designing and realizing these high-frequency circuit components. Here, we elucidate the frequency scaling law for WSe2 nanomechanical resonators by studying devices of one-, two-, three-, to more than 100-layer thicknesses and different diameters. We observe resonant responses in both mechanical limits and clear elastic transition in between, revealing intrinsic material properties and devices parameters such as Young's modulus and pretension. We further demonstrate a broad frequency tuning range (up to 230%) with a high tuning efficiency (up to 23% V-1). Such tuning efficiency is among the highest in resonators based on two-dimensional (2D) layered materials. Our findings can offer important guidelines for designing high-frequency WSe2 resonant devices.

Mechanisms in cochlear hair cell mechano-electrical transduction for acquisition of sound frequency and intensity.

Sound signals are acquired and digitized in the cochlea by the hair cells that further transmit the coded information to the central auditory pathways. Any defect in hair cell function may induce problems in the auditory system and hearing-based brain function. In the past 2 decades, our understanding of auditory transduction has been substantially deepened because of advances in molecular, structural, and functional studies. Results from these experiments can be perfectly embedded in the previously established profile from anatomical, histological, genetic, and biophysical research. This review aims to summarize the progress on the molecular and cellular mechanisms of the mechano-electrical transduction (MET) channel in the cochlear hair cells, which is involved in the acquisition of sound frequency and intensity-the two major parameters of an acoustic cue. We also discuss recent studies on TMC1, the molecule likely to form the MET channel pore.

Ultrawide Frequency Tuning of Atomic Layer van der Waals Heterostructure Electromechanical Resonators.

We report on the experimental demonstration of atomically thin molybdenum disulfide (MoS2)-graphene van der Waals (vdW) heterostructure nanoelectromechanical resonators with ultrawide frequency tuning. With direct electrostatic gate tuning, these vdW resonators exhibit exceptional tunability, in general, Δf/f0 > 200%, for continuously tuning the same device and the same mode (e.g., from ∼23 to ∼107 MHz), up to Δf/f0 ≈ 370%, the largest fractional tuning range in such resonators to date. This remarkable electromechanical resonance tuning is investigated by two different analytical models and finite element simulations. Furthermore, we carefully perform clear control experiments and simulations to elucidate the difference in frequency tuning between the heterostructure and single-material resonators. At a given initial strain level, the tuning range depends on the two-dimensional (2D) Young's moduli of the constitutive crystals; devices built on materials with lower 2D moduli show wider tuning ranges. This study exemplifies that vdW heterostructure resonators can retain unconventionally broad, continuous tuning, which is promising for voltage-controlled, tunable nanosystems.

Temporal Coding of Single Auditory Nerve Fibers Is Not Degraded in Aging Gerbils.

People suffering from age-related hearing loss typically present with deficits in temporal processing tasks. Temporal processing deficits have also been shown in single-unit studies at the level of the auditory brainstem, midbrain, and cortex of aged animals. In this study, we explored whether temporal coding is already affected at the level of the input to the central auditory system. Single-unit auditory nerve fiber recordings were obtained from 41 Mongolian gerbils of either sex, divided between young, middle-aged, and old gerbils. Temporal coding quality was evaluated as vector strength in response to tones at best frequency, and by constructing shuffled and cross-stimulus autocorrelograms, and reverse correlations, from responses to 1 s noise bursts at 10-30 dB sensation level (dB above threshold). At comparable sensation levels, all measures showed that temporal coding was not altered in auditory nerve fibers of aging gerbils. Furthermore, both temporal fine structure and envelope coding remained unaffected. However, spontaneous rates were decreased in aging gerbils. Importantly, despite elevated pure tone thresholds, the frequency tuning of auditory nerve fibers was not affected. These results suggest that age-related temporal coding deficits arise more centrally, possibly due to a loss of auditory nerve fibers (or their peripheral synapses) but not due to qualitative changes in the responses of remaining auditory nerve fibers. The reduced spontaneous rate and elevated thresholds, but normal frequency tuning, of aged auditory nerve fibers can be explained by the well known reduction of endocochlear potential due to strial dysfunction in aged gerbils.SIGNIFICANCE STATEMENT As our society ages, age-related hearing deficits become ever more prevalent. Apart from decreased hearing sensitivity, elderly people often suffer from a reduced ability to communicate in daily settings, which is thought to be caused by known age-related deficits in auditory temporal processing. The current study demonstrated, using several different stimuli and analysis techniques, that these putative temporal processing deficits are not apparent in responses of single-unit auditory nerve fibers of quiet-aged gerbils. This suggests that age-related temporal processing deficits may develop more central to the auditory nerve, possibly due to a reduced population of active auditory nerve fibers, which will be of importance for the development of treatments for age-related hearing disorders.

Effect of advancing age on inter-frequency amplitude ratio of ocular vestibular evoked myogenic potentials.

OBJECTIVE: The inter-frequency amplitude ratio (IFAR) is the ratio of the amplitude of 1000-Hz tone-burst evoked ocular vestibular evoked myogenic potential (oVEMP) to the 500 Hz tone-burst evoked oVEMP. Since IFAR is an amplitude-based parameter, and the amplitudes of oVEMP for different frequencies are differentially affected by ageing, IFAR could potentially be affected by the ageing process. Therefore, we aimed to examine the effects of ageing on the IFAR of oVEMPs. DESIGN: Multiple static groups comparison. STUDY SAMPLE: We recorded oVEMPs for 500 Hz and 1000 Hz tone-bursts from 270 healthy individuals, each included in one of the six age groups. RESULTS: The IFAR was significantly larger in the ≥60 years age group than the age groups up to 49 years. Furthermore, the IFAR in the 50-59 years age group was significantly larger than all the other age groups up to 39 years. There was a significant positive correlation between age and IFARs (p < 0.01). CONCLUSIONS: IFAR, a sensitive tool in the test battery for the diagnosis of Meniere's disease, is affected even in healthy individuals due to ageing; hence its cautious interpretation is recommended when evaluating adults >50 years of age who are suspected of having Meniere's disease.

An Electromagnetic Vibration Energy Harvester with a Tunable Mass Moment of Inertia.

This paper presents a vibration-based electromagnetic energy harvester whose resonance frequency can be adjusted to match that of the excitation. Frequency adjustment is attained by controlling a rotatable arm, with tuning masses, at the tip of a cantilever-type energy harvester, thereby changing the effective mass moment of inertia of the system. The rotatable arm is mounted on a servomotor that is autonomously controlled through a microcontroller and a photo sensor to keep the device at resonance for maximum power generation. A mathematical model is developed to predict the system response for different design parameters and to estimate the generated power. The system is investigated analytically by a distributed-parameter model to study the natural frequency variation and dynamic response. The analytical model is verified experimentally where the frequency is tuned from 8 to 10.25 Hz. A parametric study is performed to study the effect of each parameter on the system behavior.

Terahertz Emitter Using Resonant-Tunneling Diode and Applications.

A compact source is important for various applications utilizing terahertz (THz) waves. In this paper, the recent progress in resonant-tunneling diode (RTD) THz oscillators, which are compact semiconductor THz sources, is reviewed, including principles and characteristics of oscillation, studies addressing high-frequency and high output power, a structure which can easily be fabricated, frequency tuning, spectral narrowing, different polarizations, and select applications. At present, fundamental oscillation up to 1.98 THz and output power of 0.7 mW at 1 THz by a large-scale array have been reported. For high-frequency and high output power, structures integrated with cylindrical and rectangular cavities have been proposed. Using oscillators integrated with varactor diodes and their arrays, wide electrical tuning of 400-900 GHz has been demonstrated. For spectral narrowing, a line width as narrow as 1 Hz has been obtained, through use of a phase-locked loop system with a frequency-tunable oscillator. Basic research for various applications-including imaging, spectroscopy, high-capacity wireless communication, and radar systems-of RTD oscillators has been carried out. Some recent results relating to these applications are discussed.

Nonvolatile Rewritable Frequency Tuning of a Nanoelectromechanical Resonator Using Photoinduced Doping.

Arrays of nanoelectromechanical resonators (NEMS) have shown promise for a suite of applications, from nanomechanical information processing technologies to mass spectrometry. A fundamental challenge toward broader adoption of NEMS arrays is a lack of viable frequency tuning methods, which must simultaneously allow for persistent and reversible control of single resonators while also being scalable to large arrays of devices. In this work, we demonstrate an electro-optic tuning method for graphene-based NEMS where locally photoionized charge tensions a suspended membrane and tunes its resonance frequency. The tuned frequency state persists unchanged for several days in the absence of any external power, and the state can be repeatedly written and erased with a high degree of precision. We show the scalability of this technique by aligning the frequencies of several NEMS devices on the same chip, and we discuss implications of this tuning method for both single devices and programmable NEMS networks.

Approaching the Strain-Free Limit in Ultrathin Nanomechanical Resonators.

Ultrathin mechanical structures are ideal building platforms to pursue the ultimate limit of nanomechanical resonators for applications in sensing, signal processing, and quantum physics. Unfortunately, as the thickness of the vibrating structures is reduced, the built-in strain of the structural materials plays an increased role in determining the mechanical performance of the devices. As a consequence, it is very challenging to fabricate resonators working in the modulus-dominant regime, where their dynamic behavior is exclusively determined by the device geometry. In this Letter, we report ultrathin doubly clamped nanomechanical resonators with aspect ratios as large as L/t ∼5000 and working in the modulus-dominant regime. We observed room temperature thermomechanically induced motion of multiple vibration modes with resonant frequencies closely matching the predicted values of Euler-Bernoulli beam theory under an axial strain of 6.3 × 10-8. The low strain of the devices enables a record frequency tuning ratio of more than 50 times. These results illustrate a new strategy for the quantitative design of nanomechanical resonators with unprecedented performance.

Differential Inhibitory Configurations Segregate Frequency Selectivity in the Mouse Inferior Colliculus.

Receptive fields and tuning curves of sensory neurons represent the neural substrates that allow animals to efficiently detect and distinguish external stimuli. They are progressively refined to create diverse sensitivity and selectivity for neurons along ascending central pathways. However, the neural circuitry mechanisms have not been directly determined for such fundamental qualities in relation to sensory neurons' functional organizations, because of the technical difficulty of correlating neurons' input and output. Here, we obtained spike outputs and synaptic inputs from the same neurons within characteristically defined neural ensembles, to determine the synaptic mechanisms driving their diverse frequency selectivity in the mouse inferior colliculus. We find that the synaptic strength and timing of excitatory and inhibitory inputs are configured differently and independently within individual neurons' receptive fields, which segregate sensitive and selective neurons and endow neural populations with broad receptive fields and sharp frequency tuning. By computationally modeling spike outputs from integrating synaptic inputs and comparing them with real spike responses of the same neurons, we show that space-clamping errors did not qualitatively affect the estimation of spike responses derived from synaptic currents in in vivo voltage-clamp recordings. These data suggest that heterogeneous inhibitory circuits coexist locally for a parallel but differentiated representation of incoming signals.SIGNIFICANCE STATEMENT Sensitivity and selectivity are functional qualities of sensory systems to facilitate animals' survival. There is little direct evidence for the synaptic basis of neurons' functional variance within neural ensembles. Here we adopted a novel framework to fill such a long-standing gap by uniting population activities with single cells' spike outputs and their synaptic inputs. Furthermore, the effects of space-clamping errors on subcortical synaptic currents were evaluated in vivo, by comparing recorded spike responses and simulated spike outputs from computationally integrating synaptic inputs. Our study illustrated that the synaptic strength and timing of inhibition relative to excitation can be configured differently for neurons within a defined neural ensemble, to segregate their selectivity. It provides new insights into coexisting heterogeneous local circuits.

Electromagnetic Relationship between Microwaves and Flow Reactor Systems.

One of the important points in handling microwaves is that the order of magnitude is decimeter order. Laboratory equipment is not too big for wavelength, so intensity nonuniformity may occur. Another important point is that microwave propagation changes with material parameter changes. To heat material in the planned shape, the consideration with electromagnetism about the equipment and the system will be necessary. Herein, the phenomena which should be considered when a flow reactor is irradiated with a microwave is described.

Directional and frequency characteristics of auditory neurons in Culex male mosquitoes.

The paired auditory organ of the mosquito, the Johnston's organ (JO), being the receiver of the particle velocity component of sound, is directional by its structure. However, to date almost no physiological measurements of its directionality have been made. In addition, the recent finding on the grouping of the JO auditory neurons into antiphase pairs demands confirmation by different methods. Using the vector superposition of the signals produced by two orthogonally oriented speakers, we measured the directional characteristics of individual units as well as their relationships in physiologically distinguishable groups - pairs or triplets. The feedback stimulation method allowed us to discriminate responses of the two simultaneously recorded units, and to show that they indeed responded in antiphase. Units of different frequency tuning as well as highly sensitive units (thresholds of 27 dB SPVL and below) were found in every angular sector of the JO, providing the mosquito with the ability to produce complex auditory behaviors.

Objective methods to measure vestibular evoked myogenic potential response saccular tuning curves.

Objective: To detect cervical vestibular evoked myogenic potential (cVEMP) responses using objective statistical approaches and to apply this approach to estimate saccular frequency-tuning curves in volunteers and Ménière's disease (MD) patients. Design: Estimates of cVEMP threshold were carried out by 3 expert raters at 500 Hz and compared to objective threshold estimates (using Hotelling's T2 [HT2] and Fsp). Saccular tuning curves were objectively estimated. Study sample: Objective and subjective estimates of cVEMP response thresholds were compared for 13 normal hearing adults. Objective measurement of saccular tuning curves was explored in 20 healthy adults and 15 patients with MD. Results: Significant variability was seen between subjective estimates of cVEMP thresholds. Objective analysis with the HT2 test was more sensitive than 2 of 3 experts in detecting responses. The measurement time of cVEMP was considerably reduced with the HT2 test. Objective saccular tuning curves in volunteers showed strongest responses at 500 Hz. A flatter tuning curve was seen for MD patients. Conclusions: There is significant variability in subjective estimations of cVEMP thresholds. Objective analysis methods are more sensitive than subjective analysis, can detect responses rapidly and have potential to reduce variability in threshold estimates, hence they appear well suited to measure cVEMP tuning curves.