How action potentials regulate myelination by oligodendrocytes is uncertain. We show that neuronal activity raises Ca
in developing oligodendrocytes in vivo and that myelin sheath elongation is ...promoted by a high frequency of Ca
transients and prevented by Ca
buffering. Sheath elongation occurs ~1 h after Ca
elevation. Sheath shortening is associated with a low frequency of Ca
transients but with longer duration Ca
bursts. Thus, Ca
controls myelin sheath development.
Sound-evoked compound action potential (CAP), which captures the synchronous activation of the auditory nerve fibers (ANFs), is commonly used to probe deafness in experimental and clinical settings. ...All ANFs are believed to contribute to CAP threshold and amplitude: low sound pressure levels activate the high-spontaneous rate (SR) fibers, and increasing levels gradually recruit medium- and then low-SR fibers. In this study, we quantitatively analyze the contribution of the ANFs to CAP 6 days after 30-min infusion of ouabain into the round window niche. Anatomic examination showed a progressive ablation of ANFs following increasing concentration of ouabain. CAP amplitude and threshold plotted against loss of ANFs revealed three ANF pools: 1) a highly ouabain-sensitive pool, which does not participate in either CAP threshold or amplitude, 2) a less sensitive pool, which only encoded CAP amplitude, and 3) a ouabain-resistant pool, required for CAP threshold and amplitude. Remarkably, distribution of the three pools was similar to the SR-based ANF distribution (low-, medium-, and high-SR fibers), suggesting that the low-SR fiber loss leaves the CAP unaffected. Single-unit recordings from the auditory nerve confirmed this hypothesis and further showed that it is due to the delayed and broad first spike latency distribution of low-SR fibers. In addition to unraveling the neural mechanisms that encode CAP, our computational simulation of an assembly of guinea pig ANFs generalizes and extends our experimental findings to different species of mammals. Altogether, our data demonstrate that substantial ANF loss can coexist with normal hearing threshold and even unchanged CAP amplitude.
We describe the method for identification of motor unit (MU) firings from high-density surface electromyograms (hdEMG), recorded during repeated dynamic muscle contractions. A new convolutive data ...model for dynamic hdEMG is presented, along with the pulse-to-noise ratio (PNR) metric for assessment of MU identification accuracy and analysis of the impact of MU action potential (MUAP) changes in dynamic muscle contractions on MU identification. We tested the presented methodology on signals from biceps brachii, vastus lateralis, and rectus famoris muscles, all during different speeds of dynamic contractions. In synthetic signals with excitation levels of 10%, 30% and 50%, and MUAPs experimentally recorded from biceps brachii muscle, the presented method identified 15 ± 1, 18 ± 1, and 20 ± 1 MUs per contraction, respectively, all with average sensitivity and precision >90% and PNR >30dB. In experimental signals acquired during low force contractions of vastus lateralis and rectus femoris muscle, the method identified 9.4±1.9 and 7.8±1.4 MUs with PNR values of 35.4±3.6 and 34.1±2.7 dB. In comparison with the previously introduced Convolution Kernel Compensation method, the capability of the new method to follow dynamic MUAP changes is confirmed, also in relatively fast muscle contractions.
A recently discovered type of mammalian retinal ganglion cell encodes environmental light intensity and mediates non-image-forming visual behaviors, such as the pupillary reflex and circadian ...photoentrainment. These intrinsically photosensitive retinal ganglion cells (ipRGCs) generate endogenous, melanopsin-based photoresponses as well as extrinsic, rod/cone-driven responses. Because the ipRGCs' light responses and the behaviors they control are both remarkably tonic, these cells have been hypothesized to be capable of irradiance detection lasting throughout the day. I tested this hypothesis by obtaining multielectrode-array recordings from ipRGCs in a novel rat eyecup preparation that enhances the regeneration of rod/cone photopigments. I found that 10 h constant light could continuously evoke action potentials in these ganglion cells under conditions that stimulated (1) only melanopsin, (2) mainly the rod input, and (3) both intrinsic and extrinsic responses. In response to a 10 h stimulus with gradual intensity changes to simulate sunrise and sunset, ipRGC firing rates slowly increased during the "sunrise" phase and slowly decreased during the "sunset" phase. Furthermore, I recorded from putative ipRGCs of melanopsin-knock-out mice and found that these cells retained the ability to respond in a sustained fashion to 20 min light steps, indicating that melanopsin is not required for such tonic responses. In conclusion, ipRGCs can signal light continuously for at least 10 h and can probably track gradual irradiance changes over the course of the day. These results further suggest that the photoreceptors and ON bipolar cells presynaptic to ipRGCs may be able to respond to light continuously for 10 h.
Tissue engineering using cardiomyocytes derived from human pluripotent stem cells holds a promise to revolutionize drug discovery, but only if limitations related to cardiac chamber specification and ...platform versatility can be overcome. We describe here a scalable tissue-cultivation platform that is cell source agnostic and enables drug testing under electrical pacing. The plastic platform enabled on-line noninvasive recording of passive tension, active force, contractile dynamics, and Ca2+ transients, as well as endpoint assessments of action potentials and conduction velocity. By combining directed cell differentiation with electrical field conditioning, we engineered electrophysiologically distinct atrial and ventricular tissues with chamber-specific drug responses and gene expression. We report, for the first time, engineering of heteropolar cardiac tissues containing distinct atrial and ventricular ends, and we demonstrate their spatially confined responses to serotonin and ranolazine. Uniquely, electrical conditioning for up to 8 months enabled modeling of polygenic left ventricular hypertrophy starting from patient cells.
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•Positive force frequency and post-rest potentiation are achieved in human tissues•Engineered atrial and ventricular tissues have distinct electrophysiology and drug responses•Atrio-ventricular tissues show spatially confined drug responses•Long-term electrical conditioning enables polygenic cardiac disease modeling
A scalable cardiac tissue cultivation platform enables assessment of multiple parameters of atrial and ventricular tissue function, drug testing, and disease modeling.
Neuromorphic networks of artificial neurons and synapses can solve computationally hard problems with energy efficiencies unattainable for von Neumann architectures. For image processing, silicon ...neuromorphic processors outperform graphic processing units in energy efficiency by a large margin, but deliver much lower chip-scale throughput. The performance-efficiency dilemma for silicon processors may not be overcome by Moore's law scaling of silicon transistors. Scalable and biomimetic active memristor neurons and passive memristor synapses form a self-sufficient basis for a transistorless neural network. However, previous demonstrations of memristor neurons only showed simple integrate-and-fire behaviors and did not reveal the rich dynamics and computational complexity of biological neurons. Here we report that neurons built with nanoscale vanadium dioxide active memristors possess all three classes of excitability and most of the known biological neuronal dynamics, and are intrinsically stochastic. With the favorable size and power scaling, there is a path toward an all-memristor neuromorphic cortical computer.
In neurons, the axon initial segment (AIS) is a specialized region near the start of the axon that is the site of action potential initiation. The precise location of the AIS varies across and within ...different neuronal types, and has been linked to cells’ information-processing capabilities; however, the factors determining AIS position in individual neurons remain unknown. Here we show that changes in electrical activity can alter the location of the AIS. In dissociated hippocampal cultures, chronic depolarization with high extracellular potassium moves multiple components of the AIS, including voltage-gated sodium channels, up to 17 m away from the soma of excitatory neurons. This movement reverses when neurons are returned to non-depolarized conditions, and depends on the activation of T- and/or L-type voltage-gated calcium channels. The AIS also moved distally when we combined long-term LED (light-emitting diode) photostimulation with sparse neuronal expression of the light-activated cation channel channelrhodopsin-2; here, burst patterning of activity was successful where regular stimulation at the same frequency failed. Furthermore, changes in AIS position correlate with alterations in current thresholds for action potential spiking. Our results show that neurons can regulate the position of an entire subcellular structure according to their ongoing levels and patterns of electrical activity. This novel form of activity-dependent plasticity may fine-tune neuronal excitability during development.
Coordinated activity patterns in the developing brain may contribute to the wiring of neuronal circuits underlying future behavioural requirements. However, causal evidence for this hypothesis has ...been difficult to obtain owing to the absence of tools for selective manipulation of oscillations during early development. We established a protocol that combines optogenetics with electrophysiological recordings from neonatal mice in vivo to elucidate the substrate of early network oscillations in the prefrontal cortex. We show that light-induced activation of layer II/III pyramidal neurons that are transfected by in utero electroporation with a high-efficiency channelrhodopsin drives frequency-specific spiking and boosts network oscillations within beta-gamma frequency range. By contrast, activation of layer V/VI pyramidal neurons causes nonspecific network activation. Thus, entrainment of neonatal prefrontal networks in fast rhythms relies on the activation of layer II/III pyramidal neurons. This approach used here may be useful for further interrogation of developing circuits, and their behavioural readout.
Hypertrophic cardiomyopathy (HCM), the most common mendelian heart disorder, remains an orphan of disease-specific pharmacological treatment because of the limited understanding of cellular ...mechanisms underlying arrhythmogenicity and diastolic dysfunction.
We assessed the electromechanical profile of cardiomyocytes from 26 HCM patients undergoing myectomy compared with those from nonfailing nonhypertrophic surgical patients by performing patch-clamp and intracellular Ca(2+) (Ca(2+)(i)) studies. Compared with controls, HCM cardiomyocytes showed prolonged action potential related to increased late Na(+) (I(NaL)) and Ca(2+) (I(CaL)) currents and decreased repolarizing K(+) currents, increased occurrence of cellular arrhythmias, prolonged Ca(2+)(i) transients, and higher diastolic Ca(2+)(i). Such changes were related to enhanced Ca(2+)/calmodulin kinase II (CaMKII) activity and increased phosphorylation of its targets. Ranolazine at therapeutic concentrations partially reversed the HCM-related cellular abnormalities via I(NaL) inhibition, with negligible effects in controls. By shortening the action potential duration in HCM cardiomyocytes, ranolazine reduced the occurrence of early and delayed afterdepolarizations. Finally, as a result of the faster kinetics of Ca(2+)(i) transients and the lower diastolic Ca(2+)(i), ranolazine accelerated the contraction-relaxation cycle of HCM trabeculae, ameliorating diastolic function.
We highlighted a specific set of functional changes in human HCM myocardium that stem from a complex remodeling process involving alterations of CaMKII-dependent signaling, rather than being a direct consequence of the causal sarcomeric mutations. Among the several ion channel and Ca(2+)(i) handling proteins changes identified, an enhanced I(NaL) seems to be a major contributor to the electrophysiological and Ca(2+)(i) dynamic abnormalities of ventricular myocytes and trabeculae from patients with HCM, suggesting potential therapeutic implications of I(NaL) inhibition.
Fluorescence imaging is an attractive method for monitoring neuronal activity. A key challenge for optically monitoring voltage is development of sensors that can give large and fast responses to ...changes in transmembrane potential. We now present fluorescent sensors that detect voltage changes in neurons by modulation of photo-induced electron transfer (PeT) from an electron donor through a synthetic molecular wire to a fluorophore. These dyes give bigger responses to voltage than electrochromic dyes, yet have much faster kinetics and much less added capacitance than existing sensors based on hydrophobic anions or voltage-sensitive ion channels. These features enable single-trial detection of synaptic and action potentials in cultured hippocampal neurons and intact leech ganglia. Voltage-dependent PeT should be amenable to much further optimization, but the existing probes are already valuable indicators of neuronal activity.
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