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Neuroscience is experiencing a revolution in which simultaneous recording of thousands of neurons is revealing population dynamics that are not apparent from single-neuron responses. This structure is typically extracted from data averaged across many trials, but deeper understanding requires studying phenomena detected in single trials, which is challenging due to incomplete sampling of the neural population, trial-to-trial variability, and fluctuations in action potential timing. We introduce latent factor analysis via dynamical systems, a deep learning method to infer latent dynamics from single-trial neural spiking data. When applied to a variety of macaque and human motor cortical datasets, latent factor analysis via dynamical systems accurately predicts observed behavioral variables, extracts precise firing rate estimates of neural dynamics on single trials, infers perturbations to those dynamics that correlate with behavioral choices, and combines data from non-overlapping recording sessions spanning months to improve inference of underlying dynamics.

Many brain functions depend on the ability of neural networks to temporally integrate transient inputs to produce sustained discharges. This can occur through cell-autonomous mechanisms in individual neurons and through reverberating activity in recurrently connected neural networks. We report a third mechanism involving temporal integration of neural activity by a network of astrocytes. Previously, we showed that some types of interneurons can generate long-lasting trains of action potentials (barrage firing) following repeated depolarizing stimuli. Here we show that calcium signaling in an astrocytic network correlates with barrage firing; that active depolarization of astrocyte networks by chemical or optogenetic stimulation enhances; and that chelating internal calcium, inhibiting release from internal stores, or inhibiting GABA transporters or metabotropic glutamate receptors inhibits barrage firing. Thus, networks of astrocytes influence the spatiotemporal dynamics of neural networks by directly integrating neural activity and driving barrages of action potentials in some populations of inhibitory interneurons. Specific types of inhibitory neurons exhibit prolonged, high-frequency barrages of action potentials. Here, the authors show that astrocytes might mediate such barrage firing.

The proper functioning of the endoplasmic reticulum (ER) is crucial for multiple cellular activities and survival. Disturbances in the normal ER functions lead to the accumulation and aggregation of unfolded proteins, which initiates an adaptive response, the unfolded protein response (UPR), in order to regain normal ER functions. Failure to activate the adaptive response initiates the process of programmed cell death or apoptosis. Apoptosis plays an important role in cell elimination, which is essential for embryogenesis, development, and tissue homeostasis. Impaired apoptosis can lead to the development of various pathological conditions, such as neurodegenerative and autoimmune diseases, cancer, or acquired immune deficiency syndrome (AIDS). Calcium (Ca(2+)) is one of the key regulators of cell survival and it can induce ER stress-mediated apoptosis in response to various conditions. Ca(2+) regulates cell death both at the early and late stages of apoptosis. Severe Ca(2+) dysregulation can promote cell death through apoptosis. Action potential, an electrical signal transmitted along the neurons and muscle fibers, is important for conveying information to, from, and within the brain. Upon the initiation of the action potential, increased levels of cytosolic Ca(2+) (depolarization) lead to the activation of the ER stress response involved in the initiation of apoptosis. In this review, we discuss the involvement of Ca(2+) and action potential in ER stress-mediated apoptosis.

Despite ample evidence that females are weaker and possess smaller muscle cross-sectional areas (CSAs) compared to males, it remains unclear if there are sex-related differences in the properties of motor units (MU). Eleven males (age 22 ± 3 years) and 12 females (age 21 ± 1 years) performed isometric trapezoid muscle actions at 10% and 70% of maximal voluntary contraction (MVC). Surface electromyography signals were recorded and decomposed into MU action potential (AP) waveforms and firing instances. Average MUAP amplitudes (MUAPAMPS), mean firing rates (MFRs), initial firing rates (IFRs), and recruitment thresholds (RT) were calculated for the 10% MVC, while MUAPAMPS, IFRs, and MFRs were regressed against RT for the 70% MVC. Ultrasonography was used to measure CSA of the first dorsal interosseous (FDI). Males had greater CSAs (p < 0.001; males 2.34 ± 0.28 cm2, females 1.82 ± 0.18 cm2) and MVC strength (p < 0.001; males 25.9 ± 5.5 N, females 16.44 ± 2.5 N). No differences existed for MUAPAMPS, IFRs, MFRs, or RTs (p > 0.05) during the 10% MVC. For the 70% MVC, the y-intercepts from the MUAPAMPS vs. RT relationships were greater (p < 0.05) for the males (males − 0.19 ± 0.53 mV; females − 0.78 ± 0.75 mV), while the inverse was true for the MFR vs. RT relationships (males 31.55 ± 6.92 pps, females 38.65 ± 6.71 pps) with no differences (p > 0.05) in the slopes. Therefore, smaller CSAs and weaker MVCs are likely the result of smaller higher-threshold MUs for females.

Neurons undergo nanometer-scale deformations during action potentials, and the underlying mechanism has been actively debated for decades. Previous observations were limited to a single spot or the cell boundary, while movement across the entire neuron during the action potential remained unclear. Here we report full-field imaging of cellular deformations accompanying the action potential in mammalian neuron somas (−1.8 to 1.4 nm) and neurites (−0.7 to 0.9 nm), using high-speed quantitative phase imaging with a temporal resolution of 0.1 ms and an optical path length sensitivity of <4 pm per pixel. The spike-triggered average, synchronized to electrical recording, demonstrates that the time course of the optical phase changes closely matches the dynamics of the electrical signal. Utilizing the spatial and temporal correlations of the phase signals across the cell, we enhance the detection and segmentation of spiking cells compared to the shot-noise-limited performance of single pixels. Using three-dimensional (3D) cellular morphology extracted via confocal microscopy, we demonstrate that the voltage-dependent changes in the membrane tension induced by ionic repulsion can explain the magnitude, time course, and spatial features of the phase imaging. Our full-field observations of the spike-induced deformations shed light upon the electromechanical coupling mechanism in electrogenic cells and open the door to noninvasive label-free imaging of neural signaling.

Increased expression of the potassium channel Kir4.1 on astrocytes in the lateral habenula drives neuronal bursting in rodent models of depression. A burst of activity for antidepressants The lateral habenula (LHb) is a region of the brain that is associated with aversion and other negative emotions. Hailan Hu and colleagues present a pair of papers in this week's issue on the role of burst firing in LHb neurons in depression in rats. First, they show that ketamine, a drug that can be used as an antidepressant, blocks LHb neuron bursting activity, and that both NMDAR and low-voltage-sensitive T-type calcium channels (T-VSCCs) are required for the drug to be effective. In the second study, the authors identify a potential mechanism for regulating this bursting behaviour that could represent a new therapeutic target. Levels of an astroglial potassium channel, Kir4.1, covary with the degree of membrane hyperpolarization and bursting activity of LHb neurons, as well as depression-related behaviours in various rodent models. The team suggest that blocking LHb neuron bursting activity could revive reward centres in the brain and elevate mood, and provide a model framework for developing rapid-acting antidepressants. Enhanced bursting activity of neurons in the lateral habenula (LHb) is essential in driving depression-like behaviours, but the cause of this increase has been unknown. Here, using a high-throughput quantitative proteomic screen, we show that an astroglial potassium channel (Kir4.1) is upregulated in the LHb in rat models of depression. Kir4.1 in the LHb shows a distinct pattern of expression on astrocytic membrane processes that wrap tightly around the neuronal soma. Electrophysiology and modelling data show that the level of Kir4.1 on astrocytes tightly regulates the degree of membrane hyperpolarization and the amount of bursting activity of LHb neurons. Astrocyte-specific gain and loss of Kir4.1 in the LHb bidirectionally regulates neuronal bursting and depression-like symptoms. Together, these results show that a glia–neuron interaction at the perisomatic space of LHb is involved in setting the neuronal firing mode in models of a major psychiatric disease. Kir4.1 in the LHb might have potential as a target for treating clinical depression.

Severe infections like sepsis lead frequently to cardiomyopathy. The mechanisms are unclear and an optimal therapy for septic cardiomyopathy still lacks. The aim of this study is to establish an endotoxin-induced inflammatory model using human induced pluripotent stem cell (hiPSC) derived cardiomyocytes (hiPSC-CMs) for mechanistic and therapeutic studies. hiPSC-CMs were treated by lipopolysaccharide (LPS) in different concentrations for different times. ELISA, FACS, qPCR, and patch-clamp techniques were used for the study. TLR4 (Toll-like receptor 4) and its associated proteins, CD14, LBP (lipopolysaccharide binding protein), TIRAP (toll-interleukin 1 receptor domain containing adaptor protein), Ly96 (lymphocyte antigen 96) and nuclear factor kappa B as well as some pro-and anti-inflammatory factors are expressed in hiPSC-CMs. LPS-treatment for 6 hours increased the expression levels of pro-inflammatory and chemotactic cytokines (TNF-a, IL-1ß, IL-6, CCL2, CCL5, IL-8), whereas 48 hour-treatment elevated the expression of anti-inflammatory factors (IL-10 and IL-6). LPS led to cell injury resulting from exaggerated cell apoptosis and necrosis. Finally, LPS inhibited small conductance Ca 2+ -activated K + channel currents, enhanced Na + /Ca 2+ -exchanger currents, prolonged action potential duration, suggesting cellular electrical dysfunctions. Our data demonstrate that hiPSC-CMs possess the functional reaction system involved in endotoxin-induced inflammation and can model some bacterium-induced inflammatory responses in cardiac myocytes.

BackgroundMotor unit (MU) activation during maximal contractions is lower in children compared with adults. Among adults, discrete MU activation differs, depending on the rate of contraction. We investigated the effect of contraction rate on discrete MU activation in boys and men.MethodsFollowing a habituation session, 14 boys and 20 men completed two experimental sessions for knee extension and wrist flexion, in random order. Maximal voluntary isometric torque (MVIC) was determined before completing trapezoidal isometric contractions (70%MVIC) at low (10%MVIC/s) and high (35%MVIC/s) contraction rates. Surface electromyography was captured from the vastus lateralis (VL) and flexor carpi radialis (FCR) and decomposed into individual MU action potential (MUAP) trains.ResultsIn both groups and muscles, the initial MU firing rate (MUFR) was greater (p < 0.05) at high compared with low contraction rates. The increase in initial MUFR at the fast contraction in the VL was greater in men than boys (p < 0.05). Mean MUFR was significantly lower during fast contractions only in the FCR (p < 0.05). In both groups and muscles, the rate of decay of MUFR with increasing MUAP amplitude was less steep (p < 0.05) during fast compared with slow contractions.ConclusionIn both groups and muscles, initial MUFRs, as well as MUFRs of large MUs were higher during fast compared with slow contractions. However, in the VL, the increase in initial MUFR was greater in men compared with boys. This suggests that in large muscles, men may rely more on increasing MUFR to generate torque at faster rates compared with boys.

Electrode arrays are widely used for multipoint recording of electrophysiological activities, and organic electronics have been utilized to achieve both high performance and biocompatibility. However, extracellular electrode arrays record the field potential instead of the membrane potential itself, resulting in the loss of information and signal amplitude. Although much effort has been dedicated to developing intracellular access methods, their three-dimensional structures and advanced protocols prohibited implementation with organic electronics. Here, we show an organic electrochemical transistor (OECT) matrix for the intracellular action potential recording. The driving voltage of sensor matrix simultaneously causes electroporation so that intracellular action potentials are recorded with simple equipment. The amplitude of the recorded peaks was larger than that of an extracellular field potential recording, and it was further enhanced by tuning the driving voltage and geometry of OECTs. The capability of miniaturization and multiplexed recording was demonstrated through a 4 × 4 action potential mapping using a matrix of 5- × 5-μm² OECTs. Those features are realized using a mild fabrication process and a simple circuit without limiting the potential applications of functional organic electronics.

Scalable and high-throughput platforms to non-invasively record the Action Potentials (APs) of excitable cells are highly demanded to accelerate disease diagnosis and drug discovery. AP recordings are typically achieved with the invasive and low-throughput patch clamp technique. Non-invasive alternatives like planar multielectrode arrays cannot record APs without membrane poration, preventing accurate measurements of disease states and drug effects. Here, we disclose reliable and non-invasive recording of APs with patch clamp-like quality from human stem cell-derived cardiomyocytes using an inkjet-printed polymer semiconductor in an Electrolyte-Gated Field-Effect Transistor configuration. High sensitivity is proven by the detection of drug-induced pro-arrhythmic membrane potential oscillations as early/delayed afterdepolarizations. The higher throughput potential of this platform could significantly enhance disease modelling, drug screening, safety pharmacology and the study of abiotic/biotic interfaces. Scalable platforms for non-invasive action potential recording are needed. Here, the authors present a reliable method to capture APs with patch-clamp-like fidelity from stem cell-derived cardiomyocytes using an Electrolyte-Gated Polymer Field-Effect Transistors.