Sustained Stimulus Research Articles

The integrative biology of the heart: mechanisms enabling cardiac plasticity.

Cardiac phenotypic plasticity, the remodelling of heart structure and function, is a response to any sustained (or repeated) stimulus or stressor that results in a change in heart performance. Cardiac plasticity can be either adaptive (beneficial) or maladaptive (pathological), depending on the nature and intensity of the stimulus. Here, we draw on articles published in this Special Issue of Journal of Experimental Biology, and from the broader comparative physiology literature, to highlight the core components that enable cardiac plasticity, including structural remodelling, excitation-contraction coupling remodelling and metabolic rewiring. We discuss when and how these changes occur, with a focus on the underlying molecular mechanisms, from the regulation of gene transcription by epigenetic processes to post-translational modifications of cardiac proteins. Looking to the future, we anticipate that the growing use of -omics technologies in integration with traditional comparative physiology approaches will allow researchers to continue to uncover the vast scope for plasticity in cardiac function across animals.

Kif1a and intact microtubules maintain synaptic-vesicle populations at ribbon synapses in zebrafish hair cells.

Sensory hair cells of the inner ear utilize specialized ribbon synapses to transmit sensory stimuli to the central nervous system. This transmission necessitates rapid and sustained neurotransmitter release, which depends on a large pool of synaptic vesicles at the hair-cell presynapse. While previous work in neurons has shown that kinesin motor proteins traffic synaptic material along microtubules to the presynapse, the mechanisms of this process in hair cells remain unclear. Our study demonstrates that the kinesin motor protein Kif1a, along with an intact microtubule network, is essential for enriching synaptic vesicles at the presynapse in hair cells. Through genetic and pharmacological approaches, we disrupt Kif1a function and impair microtubule networks in hair cells of the zebrafish lateral-line system. These manipulations led to a significant reduction in synaptic-vesicle populations at the presynapse in hair cells. Using electron microscopy, in vivo calcium imaging, and electrophysiology, we show that a diminished supply of synaptic vesicles adversely affects ribbon-synapse function. Kif1aamutants exhibit dramatic reductions in spontaneous vesicle release and evoked postsynaptic calcium responses. Furthermore, kif1aamutants exhibit impaired rheotaxis, a behaviour reliant on the ability of hair cells in the lateral line to respond to sustained flow stimuli. Overall, our results demonstrate that Kif1a-mediated microtubule transport is critical to enrich synaptic vesicles at the active zone, a process that is vital for proper ribbon-synapse function in hair cells. KEY POINTS: Kif1a mRNAs are present in zebrafish hair cells. Loss of Kif1a disrupts the enrichment of synaptic vesicles at ribbon synapses. Disruption of microtubules depletes synaptic vesicles at ribbon synapses. Kif1aa mutants have impaired ribbon-synapse and sensory-system function.

Stimulus repetition induces a two-stage learning process in primary visual cortex.

Repeated stimulus exposure alters the brain's response to the stimulus. We investigated the underlying neural mechanisms by recording functional MRI data from human observers passively viewing 120 presentations of two Gabor patches (each Gabor repeating 60 times). We evaluated support for two prominent models of stimulus repetition, the fatigue model and the sharpening model. Our results uncovered a two-stage learning process in the primary visual cortex. In Stage 1, univariate BOLD activation in V1 decreased over the first twelve repetitions of the stimuli, replicating the well-known effect of repetition suppression. Applying MVPA decoding along with a moving window approach, we found that (1) the decoding accuracy between the two Gabors decreased from above-chance level (∼60% to ∼70%) at the beginning of the stage to chance level at the end of the stage (∼50%). This result, together with the accompanying weight map analysis, suggested that the learning dynamics in Stage 1 were consistent with the predictions of the fatigue model. In Stage 2, univariate BOLD activation for the remaining 48 repetitions of the two stimuli exhibited significant fluctuations but no systematic trend. The MVPA decoding accuracy between the two Gabor patches was at chance level initially and became progressively higher as stimulus repetition continued, rising above and staying above chance level starting at the ∼35th repetition. Thus, results from the second stage supported the notion that sustained and prolonged stimulus repetition prompts sharpened representations. Additional analyses addressed (1) whether the neural patterns within each learning stage remained stable and (2) whether new neural patterns were evoked in Stage 2 relative to Stage 1.

Deletion of the α2δ-1 calcium channel subunit increases excitability of mouse chromaffin cells.

High voltage-gated Ca2+ channels (HVCCs) shape the electrical activity and control hormone release in most endocrine cells. HVCCs are multi-subunit protein complexes formed by the pore-forming α1 and the auxiliary β, α2δ and γ subunits. Four genes code for the α2δ isoforms. At the mRNA level, mouse chromaffin cells (MCCs) express predominantly the CACNA2D1 gene coding for the α2δ-1 isoform. Here we show that α2δ-1 deletion led to ∼60% reduced HVCC Ca2+ influx with slower inactivation kinetics. Pharmacological dissection showed that HVCC composition remained similar in α2δ-1-/- MCCs compared to wild-type (WT), demonstrating that α2δ-1 exerts similar functional effects on all HVCC isoforms. Consistent with reduced HVCC Ca2+ influx, α2δ-1-/- MCCs showed reduced spontaneous electrical activity with action potentials (APs) having a shorter half-maximal duration caused by faster rising and decay slopes. However, the induced electrical activity showed opposite effects with α2δ-1-/- MCCs displaying significantly higher AP frequency in the tonic firing mode as well as an increase in the number of cells firing AP bursts compared to WT. This gain-of-function phenotype was caused by reduced functional activation of Ca2+-dependent K+ currents. Additionally, despite the reduced HVCC Ca2+ influx, the intracellular Ca2+ transients and vesicle exocytosis or endocytosis were unaltered in α2δ-1-/- MCCs compared to WT during sustained stimulation. In conclusion, our study shows that α2δ-1 genetic deletion reduces Ca2+ influx in cultured MCCs but leads to a paradoxical increase in catecholamine secretion due to increased excitability. KEY POINTS: Deletion of the α2δ-1 high voltage-gated Ca2+ channel (HVCC) subunit reduces mouse chromaffin cell (MCC) Ca2+ influx by ∼60% but causes a paradoxical increase in induced excitability. MCC intracellular Ca2+ transients are unaffected by the reduced HVCC Ca2+ influx. Deletion of α2δ-1 reduces the immediately releasable pool vesicle exocytosis but has no effect on catecholamine (CA) release in response to sustained stimuli. The increased electrical activity and CA release from MCCs might contribute to the previously reported cardiovascular phenotype of patients carrying α2δ-1 loss-of-function mutations.

What factors affect teacher professional learning: a qualitative meta-analysis based on the Onion model

Purpose Current academic research on teacher learning is increasing in number and deepening in quality, but at the same time, the heterogeneity is growing significantly. Similar work is challenging to cross-check regarding conclusions due to the different research foci. This paper aims to provide a reliable theoretical framework and offers solid insights based on the existing research. Design/methodology/approach Based on the Onion model, 67 core literature in English and Chinese were coded through qualitative meta-analysis methods to explore environmental, behavioral, competence, belief, identity, mission and other factors that may impact teacher learning. Findings It was found that the quantitative structure of the current relevant studies was in an inverted triangular shape with three levels of steps, respectively, which can be summarized as structural environment, core behaviors and dominant mission. The heterogeneity between the findings mainly originated from two situations, oppositional and complementary and some structural adjustments were made to the Onion model according to the coding results to better represent the interaction of influences between the levels. It also analyzes current research trends and the centrality of learned behaviors based on the coding results. Social implications The design of teacher learning activities should combine theoretical, practical and inquiry learning to ensure that teachers are kept fresh and motivated by sustained and varied stimuli. Originality/value To the best of the authors’ knowledge, this study is the first to analyze teacher learning influences through qualitative meta-analysis and create node saturation to analyze the results, resulting in highly credible and valuable research findings.

Cue-based modulation of pain stimulus expectation: do ongoing oscillations reflect changes in pain perception? A registered report.

A promising stream of investigations is targeting ongoing neural oscillations and whether their modulation could be related to the perception of pain. Using an electroencephalography (EEG) frequency-tagging approach, sustained periodic thermonociceptive stimuli perceived as painful have been shown to modulate ongoing oscillations in the theta, alpha and beta bands at the frequency of stimulation. Nonetheless, it remains uncertain whether these modulations are indeed linked to pain perception. To test this relationship, we modulated pain perception using a cue-based expectation modulation paradigm and investigated whether ongoing oscillations in different frequency bands mirror the changes in stimulus perception. Forty healthy participants were instructed that a visual cue can precede either a high- or low-intensity stimulation. These cues were paired with three different levels of sustained periodic thermonociceptive stimuli (low, medium and high). Despite a strong effect of expectation on perceived stimulus intensity, this effect was not reflected in the modulation of the ongoing oscillations, suggesting a potential dissociation of pain perception and these oscillatory activities. Rather, it seems that the intensity of stimulation is the primary generator of the frequency-tagged EEG responses. Importantly, these results need to be confirmed by further investigations that could allow the detection of smaller effects than originally estimated.

Kif1a and intact microtubules maintain synaptic-vesicle populations at ribbon synapses in zebrafish hair cells.

Sensory hair cells of the inner ear utilize specialized ribbon synapses to transmit sensory stimuli to the central nervous system. This sensory transmission necessitates rapid and sustained neurotransmitter release, which relies on a large pool of synaptic vesicles at the hair-cell presynapse. Work in neurons has shown that kinesin motor proteins traffic synaptic material along microtubules to the presynapse, but how new synaptic material reaches the presynapse in hair cells is not known. We show that the kinesin motor protein Kif1a and an intact microtubule network are necessary to enrich synaptic vesicles at the presynapse in hair cells. We use genetics and pharmacology to disrupt Kif1a function and impair microtubule networks in hair cells of the zebrafish lateral-line system. We find that these manipulations decrease synaptic-vesicle populations at the presynapse in hair cells. Using electron microscopy, along with in vivo calcium imaging and electrophysiology, we show that a diminished supply of synaptic vesicles adversely affects ribbon-synapse function. Kif1a mutants exhibit dramatic reductions in spontaneous vesicle release and evoked postsynaptic calcium responses. Additionally, we find that kif1a mutants exhibit impaired rheotaxis, a behavior reliant on the ability of hair cells in the lateral line to respond to sustained flow stimuli. Overall, our results demonstrate that Kif1a-based microtubule transport is critical to enrich synaptic vesicles at the active zone in hair cells, a process that is vital for proper ribbon-synapse function.

Endogenous Acetylcholine Contributes to Flow-Mediated Dilation in Humans

Background & Objective. Flow-mediated dilation (FMD) is a crucial function of the vascular endothelium wherein intraluminal shear stress stimulates endothelium-dependent vasodilation mediated primarily by nitric oxide. Brachial artery FMD (baFMD) is widely evaluated in clinical research as an index of endothelial function, and impaired baFMD is an independent predictor of cardiovascular risk. Despite the physiological and clinical relevance of FMD, the mechanisms by which shear stress is transduced to endothelium-dependent vasodilation (i.e., upstream of nitric oxide production) remain unclear. baFMD corresponds closely with sensitivity to the endothelium-dependent vasodilator acetylcholine (ACh), and preclinical models suggest ACh is released from endothelial cells in response to shear stress. Therefore, the present study tested the hypothesis that activation of muscarinic ACh receptors facilitates baFMD in humans. Methods. baFMD was evaluated using Doppler ultrasound in healthy participants (n=11; 5F/6M; 23±2 y; means ± SE) under control conditions and following local inhibition of muscarinic ACh receptors via intra-arterial atropine infused proximal to the measurement site. baFMD was assessed in response to transient and sustained shear stimuli in separate trials: 1) reactive hyperemia following 5 min of arterial cuff occlusion (RH-FMD) and 2) steady-state rhythmic handgrip exercise at graded intensities (10, 15, 20, & 25% maximal voluntary contraction, MVC) to produce step increases in shear rate (EX-FMD). Blockade effcacy was confirmed via a dose-response to intra-arterial ACh infusion pre and post atropine. Results. Baseline brachial artery diameter and forearm blood flow were similar in all trials (all P>0.05). Atropine reduced peak brachial artery dilation following cuff release (RH-FMD, Δ diameter, atropine: 4.6±0.8 vs. control: 6.5±0.8%, P=0.04) and increased the shear stimulus (shear rate area under the curve, SRAUC: atropine, 29±3 vs. control: 21±3 s−1×103, P=0.01) such that the percent change in brachial diameter was diminished by 35±16% when normalized to SRAUC (baFMD:SRAUC ratio, atropine: 1.7±0.3 vs. control: 3.9±1.0, P=0.02). Similarly, in the EX-FMD trial, atropine reduced brachial artery diameter at all exercise intensities (25% MVC, percent change in diameter: atropine, 10.8±1.4 vs. control, 15.5±1.7%, P=0.04) despite a greater shear stimulus (shear rate: atropine, 10.9±1.1 vs. control, 9.3±0.9 s−1×102, P=0.01). Thus, atropine reduced the slope describing the relationship between brachial artery vasodilation (percent change) and the change in shear rate by 38±8% across all exercise intensities (slope, atropine: 1.3±0.1 vs. control: 2.4±0.4% Δ×s×10−2, P=0.007). As expected, atropine reduced brachial artery vasodilation in response to upstream infusion of ACh (1.5 μg ACh/dl forearm volume/min, Δ diameter, atropine: 2±1 vs. control: 23±4%, P=0.001). Conclusions. The results suggest endogenous ACh facilitates baFMD in response to both transient and sustained shear stimuli, which highlights a novel physiological role of endogenous ACh in vascular regulation in humans and provides insight regarding the basic mechanisms of flow-mediated vasodilation. NIH R01 HL119337 and F31 HL142240. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Predicting early auditory evoked potentials using a computational model of auditory-nerve processing.

Non-invasive electrophysiological measures, such as auditory evoked potentials (AEPs), play a crucial role in diagnosing auditory pathology. However, the relationship between AEP morphology and cochlear degeneration remains complex and not well understood. Dau [J. Acoust. Soc. Am. 113, 936-950 (2003)] proposed a computational framework for modeling AEPs that utilized a nonlinear auditory-nerve (AN) model followed by a linear unitary response function. While the model captured some important features of the measured AEPs, it also exhibited several discrepancies in response patterns compared to the actual measurements. In this study, an enhanced AEP modeling framework is presented, incorporating an improved AN model, and the conclusions from the original study were reevaluated. Simulation results with transient and sustained stimuli demonstrated accurate auditory brainstem responses (ABRs) and frequency-following responses (FFRs) as a function of stimulation level, although wave-V latencies remained too short, similar to the original study. When compared to physiological responses in animals, the revised model framework showed a more accurate balance between the contributions of auditory-nerve fibers (ANFs) at on- and off-frequency regions to the predicted FFRs. These findings emphasize the importance of cochlear processing in brainstem potentials. This framework may provide a valuable tool for assessing human AN models and simulating AEPs for various subtypes of peripheral pathologies, offering opportunities for research and clinical applications.

Enhanced bone regeneration in rat calvarial defects through BMP2 release from engineered poly(ethylene glycol) hydrogels

The clinical standard therapy for large bone defects, typically addressed through autograft or allograft donor tissue, faces significant limitations. Tissue engineering offers a promising alternative strategy for the regeneration of substantial bone lesions. In this study, we harnessed poly(ethylene glycol) (PEG)-based hydrogels, optimizing critical parameters including stiffness, incorporation of arginine-glycine-aspartic acid (RGD) cell adhesion motifs, degradability, and the release of BMP2 to promote bone formation. In vitro we demonstrated that human bone marrow derived stromal cell (hBMSC) proliferation and spreading strongly correlates with hydrogel stiffness and adhesion to RGD peptide motifs. Moreover, the incorporation of the osteogenic growth factor BMP2 into the hydrogels enabled sustained release, effectively inducing bone regeneration in encapsulated progenitor cells. When used in vivo to treat calvarial defects in rats, we showed that hydrogels of low and intermediate stiffness optimally facilitated cell migration, proliferation, and differentiation promoting the efficient repair of bone defects. Our comprehensive in vitro and in vivo findings collectively suggest that the developed hydrogels hold significant promise for clinical translation for bone repair and regeneration by delivering sustained and controlled stimuli from active signaling molecules.

Functional dissection of parabrachial substrates in processing nociceptive information.

Painful stimuli elicit first-line reflexive defensive reactions and, in many cases, also evoke second-line recuperative behaviors, the latter of which reflects the sensing of tissue damage and the alleviation of suffering. The lateral parabrachial nucleus (lPBN), composed of external- (elPBN), dorsal- (dlPBN), and central/superior-subnuclei (jointly referred to as slPBN), receives sensory inputs from spinal projection neurons and plays important roles in processing affective information from external threats and body integrity disruption. However, the organizational rules of lPBN neurons that provoke diverse behaviors in response to different painful stimuli from cutaneous and deep tissues remain unclear. In this study, we used region-specific neuronal depletion or silencing approaches combined with a battery of behavioral assays to show that slPBN neurons expressing substance P receptor ( NK1R) (lPBN NK1R) are crucial for driving pain-associated self-care behaviors evoked by sustained noxious thermal and mechanical stimuli applied to skin or bone/muscle, while elPBN neurons are dispensable for driving such reactions. Notably, lPBN NK1R neurons are specifically required for forming sustained somatic pain-induced negative teaching signals and aversive memory but are not necessary for fear-learning or escape behaviors elicited by external threats. Lastly, both lPBN NK1R and elPBN neurons contribute to chemical irritant-induced nocifensive reactions. Our results reveal the functional organization of parabrachial substrates that drive distinct behavioral outcomes in response to sustained pain versus external danger under physiological conditions.

Promotion of Associativism for Family Production in Argentina and Uruguay (2003-2019)

In both Argentina and Uruguay, the agricultural policy of the progressive governments has evidenced two facets: a sustained stimulus to the expansion of agribusiness and a series of compensatory policies for family production and rural wage earners. Within this set, the study focuses on policies to promote associativism in family farming. In particular, it reconstructs the objectives, recipients, and implementation strategies in the territory of rural development programs. The quantitative impact that these programs had on the construction of the network of associations of family producers is also preliminarily. The work is part of agrarian history in a comparative key. It allows a narration that advances in the recognition of the general tendencies that the progressive governments of both sides of the Río de la Plata evidenced for the attention of the most vulnerable sectors of the agrarian structure, based on the complexity of the political-institutional framework and the rural world of each one of the countries involved.

Reproducible and fully automated testing of nocifensive behavior in mice

Pain in rodents is often inferred from their withdrawal from noxious stimulation. Threshold stimulus intensity or response latency is used to quantify pain sensitivity. This usually involves applying stimuli by hand and measuring responses by eye, which limits reproducibility and throughput. We describe a device that standardizes and automates pain testing by providing computer-controlled aiming, stimulation, and response measurement. Optogenetic and thermal stimuli are applied using blue and infrared light, respectively. Precise mechanical stimulation is also demonstrated. Reflectance of red light is used to measure paw withdrawal with millisecond precision. We show that consistent stimulus delivery is crucial for resolving stimulus-dependent variations in withdrawal and for testing with sustained stimuli. Moreover, substage video reveals "spontaneous" behaviors for consideration alongside withdrawal metrics to better assess the pain experience. The entire process was automated using machine learning. RAMalgo (reproducible automated multimodal algometry) improves the standardization, comprehensiveness, and throughput of preclinical pain testing.

Combined transcranial magnetic stimulation and electroencephalography reveals alterations in cortical excitability during pain.

Transcranial magnetic stimulation (TMS) has been used to examine inhibitory and facilitatory circuits during experimental pain and in chronic pain populations. However, current applications of TMS to pain have been restricted to measurements of motor evoked potentials (MEPs) from peripheral muscles. Here, TMS was combined with electroencephalography (EEG) to determine whether experimental pain could induce alterations in cortical inhibitory/facilitatory activity observed in TMS-evoked potentials (TEPs). In Experiment 1 (n=29), multiple sustained thermal stimuli were administered to the forearm, with the first, second, and third block of thermal stimuli consisting of warm but non-painful (pre-pain block), painful (pain block) and warm but non-painful (post-pain block) temperatures, respectively. During each stimulus, TMS pulses were delivered while EEG (64 channels) was simultaneously recorded. Verbal pain ratings were collected between TMS pulses. Relative to pre-pain warm stimuli, painful stimuli led to an increase in the amplitude of the frontocentral negative peak ~45 ms post-TMS (N45), with a larger increase associated with higher pain ratings. Experiments 2 and 3 (n=10 in each) showed that the increase in the N45 in response to pain was not due to changes in sensory potentials associated with TMS, or a result of stronger reafferent muscle feedback during pain. This is the first study to use combined TMS-EEG to examine alterations in cortical excitability in response to pain. These results suggest that the N45 TEP peak, which indexes GABAergic neurotransmission, is implicated in pain perception and is a potential marker of individual differences in pain sensitivity.

Introducing the STReaC (Spike Train Response Classification) toolbox

Background:This work presents a toolbox that implements methodology for automated classification of diverse neural responses to optogenetic stimulation or other changes in conditions, based on spike train recordings. New Method:The toolbox implements what we call the Spike Train Response Classification algorithm (STReaC), which compares measurements of activity during a baseline period with analogous measurements during a subsequent period to identify various responses that might result from an event such as introduction of a sustained stimulus. The analyzed response types span a variety of patterns involving distinct time courses of increased firing, or excitation, decreased firing, or inhibition, or combinations of these. Excitation (inhibition) is identified from a comparative analysis of the spike density function (interspike interval function) for the baseline period relative to the corresponding function for the response period. Results:The STReaC algorithm as implemented in this toolbox provides a user-friendly, tunable, objective methodology that can detect a variety of neuronal response types and associated subtleties. We demonstrate this with single-unit neural recordings of rodent substantia nigra pars reticulata (SNr) during optogenetic stimulation of the globus pallidus externa (GPe). Comparison with existing methods:In several examples, we illustrate how the toolbox classifies responses in situations in which traditional methods (spike counting and visual inspection) either fail to detect a response or provide a false positive. Conclusions:The STReaC toolbox provides a simple, efficient approach for classifying spike trains into a variety of response types defined relative to a period of baseline spiking.

A Deep-Learning Driven Investigation of the Circuit Basis for Reflexive Hypersensitivity to Thermal Pain.

Objectively measuring animal behavior is vital to understanding the neural circuits underlying pain. Recent progress in machine vision has presented unprecedented scope in behavioral analysis. Here, we apply DeepLabCut (DLC) to dissect mouse behavior on the thermal-plate test - a commonly used paradigm to ascertain supraspinal contributions to noxious thermal sensation and pain hypersensitivity. We determine the signature characteristics of the pattern of mouse movement and posture in 3D in response to a range of temperatures from innocuous to noxious on the thermal-plate test. Next, we test how acute chemical and chronic inflammatory injuries sensitize mouse behaviors. Repeated exposure to noxious temperatures on the thermal plate can induce learning. In this study, we design a novel assay and formulate an analytical pipeline to facilitate the dissection of plasticity mechanisms in pain circuits in the brain. Last, we record and test how activating Tacr1 expressing PBN neurons (PBNTacr1) - a population responsive to sustained noxious stimuli- affects mouse behavior on the thermal plate test. Taken together, we demonstrate that by tracking a single body part of a mouse, we can reveal the behavioral signatures of mice exposed to noxious surface temperatures, report the alterations of the same when injured, and determine if a molecularly and anatomically defined pain-responsive circuit plays a role in the reflexive hypersensitivity to thermal pain.

A Dual-Antioxidative Coating on Transmucosal Component of Implant to Repair Connective Tissue Barrier for Treatment of Peri-Implantitis.

Since the microgap between implant and surrounding connective tissue creates the pass for pathogen invasion, sustained pathological stimuli can accelerate macrophage-mediated inflammation, therefore affecting peri-implant tissue regeneration and aggravate peri-implantitis. As the transmucosal component of implant, the abutment therefore needs to be biofunctionalized to repair the gingival barrier. Here, a mussel-bioinspired implant abutment coating containing tannic acid (TA), cerium and minocycline (TA-Ce-Mino) is reported. TA provides pyrogallol and catechol groups to promote cell adherence. Besides, Ce3+ /Ce4+ conversion exhibits enzyme-mimetic activity to remove reactive oxygen species while generating O2 , therefore promoting anti-inflammatory M2 macrophage polarization to help create a regenerative environment. Minocycline isinvolved on the TA surface to create local drug storage for responsiveantibiosis. Moreover, the underlying therapeutic mechanism is revealed whereby the coating exhibits exogenous antioxidation from the inherent properties of Ce and TA and endogenous antioxidation through mitochondrial homeostasis maintenance and antioxidases promotion. In addition, it stimulates integrin to activate PI3K/Akt and RhoA/ROCK pathways to enhance VEGF-mediated angiogenesis and tissue regeneration. Combining the antibiosis and multidimensional orchestration, TA-Ce-Mino repairs soft tissue barriers and effector cell differentiation, thereby isolating the immune microenvironment from pathogen invasion. Consequently, this study provides critical insight into the design and biological mechanism of abutment surface modification to prevent peri-implantitis.

Mechanisms of PIEZO Channel Inactivation.

PIEZO channels PIEZO1 and PIEZO2 are the newly identified mechanosensitive, non-selective cation channels permeable to Ca2+. In higher vertebrates, PIEZO1 is expressed ubiquitously in most tissues and cells while PIEZO2 is expressed more specifically in the peripheral sensory neurons. PIEZO channels contribute to a wide range of biological behaviors and developmental processes, therefore driving significant attention in the effort to understand their molecular properties. One prominent property of PIEZO channels is their rapid inactivation, which manifests itself as a decrease in channel open probability in the presence of a sustained mechanical stimulus. The lack of the PIEZO channel inactivation is linked to various mechanopathologies emphasizing the significance of studying this PIEZO channel property and the factors affecting it. In the present review, we discuss the mechanisms underlying the PIEZO channel inactivation, its modulation by the interaction of the channels with lipids and/or proteins, and how the changes in PIEZO inactivation by the channel mutations can cause a variety of diseases in animals and humans.

Neuropeptide Y Signaling Regulates Recurrent Excitation in the Auditory Midbrain.

Neuropeptides play key roles in shaping the organization and function of neuronal circuits. In the inferior colliculus (IC), which is in the auditory midbrain, Neuropeptide Y (NPY) is expressed by a class of GABAergic neurons that project locally and outside the IC. Most neurons in the IC have local axon collaterals; however, the organization and function of local circuits in the IC remain unknown. We previously found that excitatory neurons in the IC can express the NPY Y1 receptor (Y1R+) and application of the Y1R agonist, [Leu31, Pro34]-NPY (LP-NPY), decreases the excitability of Y1R+ neurons. As NPY signaling regulates recurrent excitation in other brain regions, we hypothesized that Y1R+ neurons form interconnected local circuits in the IC and that NPY decreases the strength of recurrent excitation in these circuits. To test this hypothesis, we used optogenetics to activate Y1R+ neurons in mice of both sexes while recording from other neurons in the ipsilateral IC. We found that nearly 80% of glutamatergic IC neurons express the Y1 receptor, providing extensive opportunities for NPY signaling to regulate local circuits. Additionally, Y1R+ neuron synapses exhibited modest short-term synaptic plasticity, suggesting that local excitatory circuits maintain their influence over computations during sustained stimuli. We further found that application of LP-NPY decreased recurrent excitation in the IC, suggesting that NPY signaling strongly regulates local circuit function in the auditory midbrain. Our findings show that Y1R+ excitatory neurons form interconnected local circuits in the IC, and their influence over local circuits is regulated by NPY signaling.SIGNIFICANCE STATEMENT Local networks play fundamental roles in shaping neuronal computations in the brain. The IC, localized in the auditory midbrain, plays an essential role in sound processing, but the organization of local circuits in the IC is largely unknown. Here, we show that IC neurons that express the Neuropeptide Y1 receptor (Y1R+ neurons) make up most of the excitatory neurons in the IC and form interconnected local circuits. Additionally, we found that NPY, which is a powerful neuromodulator known to shape neuronal activity in other brain regions, decreases the extensive recurrent excitation mediated by Y1R+ neurons in local IC circuits. Thus, our results suggest that local NPY signaling is a key regulator of auditory computations in the IC.

The role of ongoing oscillation in pain perception: Absence of modulation by a concomitant arithmetic task

Sustained nociceptive stimuli have been shown to modulate the amplitude of ongoing neural oscillations in the theta, alpha and beta frequency bands at the frequency of stimulation, suggesting a relationship between these ongoing oscillations and pain perception. Yet, whether these ongoing oscillations are actually related to the pain experience remains unclear. If it were the case, then cognitive processes that are known to affect pain intensity should also affect these ongoing oscillations. To this end, we used electroencephalography (EEG) to investigate whether distraction – an attentional state known to affect pain perception – also modulates the amplitude of these neural oscillations. More specifically, we hypothesized that performing an unrelated arithmetic task during sustained nociceptive stimulation would lead to a decrease in the modulations of ongoing oscillations exerted by the stimulation. To assess the selectivity of this modulation for nociception, we compared the modulations of ongoing oscillations exerted by sustained periodic thermonociceptive and non-nociceptive vibrotactile stimulation (.2 Hz, 75 sec), while participants were either asked to solve an unrelated arithmetic task (distraction task) or received no specific instruction (baseline). The intensity of perception was significantly reduced by the arithmetic task in both the thermonociceptive and the vibrotactile modality, and the sustained periodic stimulation elicited a periodic response at the frequency of stimulation in both modalities. However, the distraction task did not show a differential effect for the two stimulation modalities in any of the frequency bands. The fact that, unlike pain perception, these oscillations did not appear to be affected by the task suggests that they are dissociable from pain perception. Whether a different task (leading to a stronger degree of distraction) could lead to different results is unclear.