scholarly journals Sodium channels implement a molecular leaky integrator that detects action potentials and regulates neuronal firing

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Marco A Navarro ◽  
Autoosa Salari ◽  
Jenna L Lin ◽  
Luke M Cowan ◽  
Nicholas J Penington ◽  
...  
Keyword(s):  
Sodium Channels ◽  
Action Potentials ◽  
Critical Role ◽  
Low Frequency ◽  
Kinetic Mechanism ◽  
Excitatory Input ◽  
Neuronal Firing ◽  
Na Current ◽  
Brain Functions ◽  
Leaky Integrator

Voltage-gated sodium channels play a critical role in cellular excitability, amplifying small membrane depolarizations into action potentials. Interactions with auxiliary subunits and other factors modify the intrinsic kinetic mechanism to result in new molecular and cellular functionality. We show here that sodium channels can implement a molecular leaky integrator, where the input signal is the membrane potential and the output is the occupancy of a long-term inactivated state. Through this mechanism, sodium channels effectively measure the frequency of action potentials and convert it into Na+ current availability. In turn, the Na+ current can control neuronal firing frequency in a negative feedback loop. Consequently, neurons become less sensitive to changes in excitatory input and maintain a lower firing rate. We present these ideas in the context of rat serotonergic raphe neurons, which fire spontaneously at low frequency and provide critical neuromodulation to many autonomous and cognitive brain functions.

scholarly journals Author response: Sodium channels implement a molecular leaky integrator that detects action potentials and regulates neuronal firing

2020 ◽  
Author(s):  
Marco A Navarro ◽  
Autoosa Salari ◽  
Jenna L Lin ◽  
Luke M Cowan ◽  
Nicholas J Penington ◽  
...  
Keyword(s):  
Sodium Channels ◽  
Action Potentials ◽  
Neuronal Firing ◽  
Author Response ◽  
Leaky Integrator

scholarly journals Sodium Channels Implement a Molecular Leaky Integrator to Sense Spiking Frequency and Regulate Neuronal Firing

2019 ◽  
Vol 116 (3) ◽  
pp. 388a
Author(s):  
Marco A. Navarro ◽  
Jenna Lin ◽  
Autoosa Salari ◽  
Mirela Milescu ◽  
Lorin S. Milescu
Keyword(s):  
Sodium Channels ◽  
Neuronal Firing ◽  
Leaky Integrator

scholarly journals Two Novel Peptide Toxins from the Spider Cyriopagopus longipes Inhibit Tetrodotoxin-Sensitive Sodium Channels

Toxins ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 529
Author(s):  
Qingfeng Zhang ◽  
Yuxin Si ◽  
Li Yang ◽  
Li Wang ◽  
Shuijiao Peng ◽  
...  
Keyword(s):  
Sodium Channels ◽  
Action Potentials ◽  
Inhibitory Concentration ◽  
Pharmacological Study ◽  
Critical Role ◽  
Site Directed Mutagenesis ◽  
Channel Activation ◽  
Peptide Toxins ◽  
A Site ◽  
Animal Venoms

Sodium channels play a critical role in the generation and propagation of action potentials in excitable tissues, such as nerves, cardiac muscle, and skeletal muscle, and are the primary targets of toxins found in animal venoms. Here, two novel peptide toxins (Cl6a and Cl6b) were isolated from the venom of the spider Cyriopagopus longipes and characterized. Cl6a and Cl6b were shown to be inhibitors of tetrodotoxin-sensitive (TTX-S), but not TTX-resistant, sodium channels. Among the TTX-S channels investigated, Cl6a and Cl6b showed the highest degree of inhibition against NaV1.7 (half-maximal inhibitory concentration (IC50) of 11.0 ± 2.5 nM and 18.8 ± 2.4 nM, respectively) in an irreversible manner that does not alter channel activation, inactivation, or repriming kinetics. Moreover, analysis of NaV1.7/NaV1.8 chimeric channels revealed that Cl6b is a site 4 neurotoxin. Site-directed mutagenesis analysis indicated that D816, V817, and E818 observably affected the efficacy of the Cl6b-NaV1.7 interaction, suggesting that these residues might directly affect the interaction of NaV1.7 with Cl6b. Taken together, these two novel peptide toxins act as potent and sustained NaV1.7 blockers and may have potential in the pharmacological study of sodium channels.

scholarly journals Protective Effect of Osmundacetone against Neurological Cell Death Caused by Oxidative Glutamate Toxicity

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 328
Author(s):  
Tuy An Trinh ◽  
Young Hye Seo ◽  
Sungyoul Choi ◽  
Jun Lee ◽  
Ki Sung Kang
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Defense Mechanism ◽  
Neuroprotective Effect ◽  
Glutamate Release ◽  
Chromatin Condensation ◽  
Critical Role ◽  
Glutamate Toxicity ◽  
Heme Oxygenase 1 ◽  
Brain Functions

Oxidative stress is one of the main causes of brain cell death in neurological disorders. The use of natural antioxidants to maintain redox homeostasis contributes to alleviating neurodegeneration. Glutamate is an excitatory neurotransmitter that plays a critical role in many brain functions. However, excessive glutamate release induces excitotoxicity and oxidative stress, leading to programmed cell death. Our study aimed to evaluate the effect of osmundacetone (OAC), isolated from Elsholtzia ciliata (Thunb.) Hylander, against glutamate-induced oxidative toxicity in HT22 hippocampal cells. The effect of OAC treatment on excess reactive oxygen species (ROS), intracellular calcium levels, chromatin condensation, apoptosis, and the expression level of oxidative stress-related proteins was evaluated. OAC showed a neuroprotective effect against glutamate toxicity at a concentration of 2 μM. By diminishing the accumulation of ROS, as well as stimulating the expression of heat shock protein 70 (HSP70) and heme oxygenase-1 (HO-1), OAC triggered the self-defense mechanism in neuronal cells. The anti-apoptotic effect of OAC was demonstrated through its inhibition of chromatin condensation, calcium accumulation, and reduction of apoptotic cells. OAC significantly suppressed the phosphorylation of mitogen-activated protein kinases (MAPKs), including c-Jun NH2-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and p38 kinases. Thus, OAC could be a potential agent for supportive treatment of neurodegenerative diseases.

Preparing for the unpredictable: adaptive feedback enhances the response to unexpected communication signals

2012 ◽  
Vol 107 (4) ◽  
pp. 1241-1246 ◽  
Author(s):  
Gary Marsat ◽  
Leonard Maler
Keyword(s):  
Nervous System ◽  
Sensory Input ◽  
Low Frequency ◽  
Excitatory Input ◽  
Negative Image ◽  
Communication Signals ◽  
First Order ◽  
Communication Signal ◽  
Apical Dendrites ◽  
Spike Bursts

To interact with the environment efficiently, the nervous system must generate expectations about redundant sensory signals and detect unexpected ones. Neural circuits can, for example, compare a prediction of the sensory signal that was generated by the nervous system with the incoming sensory input, to generate a response selective to novel stimuli. In the first-order electrosensory neurons of a gymnotiform electric fish, a negative image of low-frequency redundant communication signals is subtracted from the neural response via feedback, allowing unpredictable signals to be extracted. Here we show that the cancelling feedback not only suppresses the predictable signal but also actively enhances the response to the unpredictable communication signal. A transient mismatch between the predictive feedback and incoming sensory input causes both to be positive: the soma is suddenly depolarized by the unpredictable input, whereas the neuron's apical dendrites remain depolarized by the lagging cancelling feedback. The apical dendrites allow the backpropagation of somatic spikes. We show that backpropagation is enhanced when the dendrites are depolarized, causing the unpredictable excitatory input to evoke spike bursts. As a consequence, the feedback driven by a predictable low-frequency signal not only suppresses the response to a redundant stimulus but also induces a bursting response triggered by unpredictable communication signals.

Basis for tetrodotoxin and lidocaine effects on action potentials in dog ventricular myocytes

1988 ◽  
Vol 254 (6) ◽  
pp. H1157-H1166 ◽  
Author(s):  
J. A. Wasserstrom ◽  
J. J. Salata
Keyword(s):  
Action Potential ◽  
Action Potentials ◽  
Ventricular Myocytes ◽  
Ionic Currents ◽  
Detectable Effect ◽  
Na Channel ◽  
Na Current ◽  
Voltage Range ◽  
Purkinje Fibers ◽  
Ventricular Cells

We studied the effects of tetrodotoxin (TTX) and lidocaine on transmembrane action potentials and ionic currents in dog isolated ventricular myocytes. TTX (0.1-1 x 10(-5) M) and lidocaine (0.5-2 x 10(-5) M) decreased action potential duration, but only TTX decreased the maximum rate of depolarization (Vmax). Both TTX (1-2 x 10(-5) M) and lidocaine (2-5 x 10(-5) M) blocked a slowly inactivating toward current in the plateau voltage range. The voltage- and time-dependent characteristics of this current are virtually identical to those described in Purkinje fibers for the slowly inactivating inward Na+ current. In addition, TTX abolished the outward shift in net current at plateau potentials caused by lidocaine alone. Lidocaine had no detectable effect on the slow inward Ca2+ current and the inward K+ current rectifier, Ia. Our results indicate that 1) there is a slowly inactivating inward Na+ current in ventricular cells similar in time, voltage, and TTX sensitivity to that described in Purkinje fibers; 2) both TTX and lidocaine shorten ventricular action potentials by reducing this slowly inactivating Na+ current; 3) lidocaine has no additional actions on other ionic currents that contribute to its ability to abbreviate ventricular action potentials; and 4) although both agents shorten the action potential by the same mechanism, only TTX reduces Vmax. This last point suggests that TTX produces tonic block of Na+ current, whereas lidocaine may produce state-dependent Na+ channel block, namely, blockade of Na+ current only after Na+ channels have already been opened (inactivated-state block).

scholarly journals Disparity in interaural time difference improves the accuracy of neural representations of individual concurrent narrowband sounds in rat inferior colliculus and auditory cortex

2020 ◽  
Vol 123 (2) ◽  
pp. 695-706
Author(s):  
Lu Luo ◽  
Na Xu ◽  
Qian Wang ◽  
Liang Li
Keyword(s):  
Auditory Cortex ◽  
Inferior Colliculus ◽  
Interaural Time Difference ◽  
Critical Role ◽  
Low Frequency ◽  
Time Difference ◽  
Neural Representation ◽  
Frequency Bands ◽  
Neural Segregation ◽  
Peripheral Auditory System

The central mechanisms underlying binaural unmasking for spectrally overlapping concurrent sounds, which are unresolved in the peripheral auditory system, remain largely unknown. In this study, frequency-following responses (FFRs) to two binaurally presented independent narrowband noises (NBNs) with overlapping spectra were recorded simultaneously in the inferior colliculus (IC) and auditory cortex (AC) in anesthetized rats. The results showed that for both IC FFRs and AC FFRs, introducing an interaural time difference (ITD) disparity between the two concurrent NBNs enhanced the representation fidelity, reflected by the increased coherence between the responses evoked by double-NBN stimulation and the responses evoked by single NBNs. The ITD disparity effect varied across frequency bands, being more marked for higher frequency bands in the IC and lower frequency bands in the AC. Moreover, the coherence between IC responses and AC responses was also enhanced by the ITD disparity, and the enhancement was most prominent for low-frequency bands and the IC and the AC on the same side. These results suggest a critical role of the ITD cue in the neural segregation of spectrotemporally overlapping sounds. NEW & NOTEWORTHY When two spectrally overlapped narrowband noises are presented at the same time with the same sound-pressure level, they mask each other. Introducing a disparity in interaural time difference between these two narrowband noises improves the accuracy of the neural representation of individual sounds in both the inferior colliculus and the auditory cortex. The lower frequency signal transformation from the inferior colliculus to the auditory cortex on the same side is also enhanced, showing the effect of binaural unmasking.

scholarly journals The Old and the New: Can Physics-Informed Deep-Learning Replace Traditional Linear Solvers?

2021 ◽  
Vol 4 ◽  
Author(s):  
Stefano Markidis
Keyword(s):  
Neural Networks ◽  
Deep Learning ◽  
High Performance ◽  
Critical Role ◽  
Low Frequency ◽  
Accurate Solution ◽  
Limiting Factor ◽  
Data Set ◽  
Linear Solvers ◽  
Computational Performance

Physics-Informed Neural Networks (PINN) are neural networks encoding the problem governing equations, such as Partial Differential Equations (PDE), as a part of the neural network. PINNs have emerged as a new essential tool to solve various challenging problems, including computing linear systems arising from PDEs, a task for which several traditional methods exist. In this work, we focus first on evaluating the potential of PINNs as linear solvers in the case of the Poisson equation, an omnipresent equation in scientific computing. We characterize PINN linear solvers in terms of accuracy and performance under different network configurations (depth, activation functions, input data set distribution). We highlight the critical role of transfer learning. Our results show that low-frequency components of the solution converge quickly as an effect of the F-principle. In contrast, an accurate solution of the high frequencies requires an exceedingly long time. To address this limitation, we propose integrating PINNs into traditional linear solvers. We show that this integration leads to the development of new solvers whose performance is on par with other high-performance solvers, such as PETSc conjugate gradient linear solvers, in terms of performance and accuracy. Overall, while the accuracy and computational performance are still a limiting factor for the direct use of PINN linear solvers, hybrid strategies combining old traditional linear solver approaches with new emerging deep-learning techniques are among the most promising methods for developing a new class of linear solvers.

scholarly journals A sensory integration account for time perception

2020 ◽  
Author(s):  
Alessandro Toso ◽  
Arash Fassihi ◽  
Luciano Paz ◽  
Francesca Pulecchi ◽  
Mathew E. Diamond
Keyword(s):  
Time Perception ◽  
Time Constant ◽  
Sensory Integration ◽  
Neuronal Firing ◽  
Elapsed Time ◽  
Leaky Integrator ◽  
Long Time ◽  
Integrator Model ◽  
Short Time ◽  
Sense Of Touch

ABSTRACTThe connection between stimulus perception and time perception remains unknown. The present study combines human and rat psychophysics with sensory cortical neuronal firing to construct a computational model for the percept of elapsed time embedded within sense of touch. When subjects judged the duration of a vibration applied to the fingertip (human) or whiskers (rat), increasing stimulus mean speed led to increasing perceived duration. Symmetrically, increasing vibration duration led to increasing perceived intensity. We modeled spike trains from vibrissal somatosensory cortex as input to dual leaky integrators – an intensity integrator with short time constant and a duration integrator with long time constant – generating neurometric functions that replicated the actual psychophysical functions of rats. Returning to human psychophysics, we then confirmed specific predictions of the dual leaky integrator model. This study offers a framework, based on sensory coding and subsequent accumulation of sensory drive, to account for how a feeling of the passage of time accompanies the tactile sensory experience.

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