scholarly journals Nonthermal and reversible control of neuronal signaling and behavior by midinfrared stimulation

2021 ◽  
Vol 118 (10) ◽  
pp. e2015685118
Author(s):  
Xi Liu ◽  
Zhi Qiao ◽  
Yuming Chai ◽  
Zhi Zhu ◽  
Kaijie Wu ◽  
...  
Keyword(s):  
Ion Selectivity ◽  
Gain Control ◽  
Pyramidal Cells ◽  
Output Curve ◽  
Patch Clamp Recording ◽  
Long Distance ◽  
Current Increase ◽  
Neuronal Signaling ◽  
Brain Functions ◽  
Dynamics Simulations

Various neuromodulation approaches have been employed to alter neuronal spiking activity and thus regulate brain functions and alleviate neurological disorders. Infrared neural stimulation (INS) could be a potential approach for neuromodulation because it requires no tissue contact and possesses a high spatial resolution. However, the risk of overheating and an unclear mechanism hamper its application. Here we show that midinfrared stimulation (MIRS) with a specific wavelength exerts nonthermal, long-distance, and reversible modulatory effects on ion channel activity, neuronal signaling, and sensorimotor behavior. Patch-clamp recording from mouse neocortical pyramidal cells revealed that MIRS readily provides gain control over spiking activities, inhibiting spiking responses to weak inputs but enhancing those to strong inputs. MIRS also shortens action potential (AP) waveforms by accelerating its repolarization, through an increase in voltage-gated K+ (but not Na+) currents. Molecular dynamics simulations further revealed that MIRS-induced resonance vibration of –C=O bonds at the K+ channel ion selectivity filter contributes to the K+ current increase. Importantly, these effects are readily reversible and independent of temperature increase. At the behavioral level in larval zebrafish, MIRS modulates startle responses by sharply increasing the slope of the sensorimotor input–output curve. Therefore, MIRS represents a promising neuromodulation approach suitable for clinical application.

scholarly journals Multiple Synaptic Connections Into a Single Cortical Pyramidal Cell or Interneuron in the Anterior Cingulate Cortex of Adult Mice

2021 ◽  
Author(s):  
Jung-Hyun Alex Lee ◽  
Zhuang Miao ◽  
Qi-Yu Chen ◽  
Xu-Hui Li ◽  
Min Zhuo
Keyword(s):  
Single Neuron ◽  
Molecular Mechanisms ◽  
Pyramidal Neurons ◽  
Field Potential ◽  
Pyramidal Cells ◽  
Anterior Cingulate ◽  
Mapping Technique ◽  
Synaptic Connections ◽  
Patch Clamp Recording ◽  
Brain Functions

Abstract The ACC is an important brain area for the processing of pain-related information. Studies of synaptic connections within the ACC provide an understanding of basic cellular and molecular mechanisms for brain functions such as pain, emotion and related cognitive functions. Previous study of ACC synaptic transmission mainly focused on presumably thalamic inputs into pyramidal cells. In the present study, we developed a new mapping technique by combining single neuron whole-cell patch-clamp recording with 64 multi-channel field potential recording (MED64) to examine the properties of excitatory inputs into a single neuron in the ACC. We found that a single patched pyramidal neuron or interneuron simultaneously received heterogeneous excitatory synaptic innervations from different subregions (ventral, dorsal, deep, and superficial layers) in the ACC. Conduction velocity is faster as stimulation distance increases in pyramidal neurons. Fast-spiking interneurons (FS-IN) show slower inactivation when compared to pyramidal neurons and regular-spiking interneurons (RS-IN) while pyramidal neurons displayed the most rapid activation. Bath application of non-competitive AMPA receptor antagonist GYKI 53655 followed by CNQX revealed that both FS-INs and RS-INs have AMPA and KA mediated components. Our studies provide a new strategy and technique for studying the network of synaptic connections.

scholarly journals Multiple synaptic connections into a single cortical pyramidal cell or interneuron in the anterior cingulate cortex of adult mice

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Jung-Hyun Alex Lee ◽  
Zhuang Miao ◽  
Qi-Yu Chen ◽  
Xu-Hui Li ◽  
Min Zhuo
Keyword(s):  
Single Neuron ◽  
Molecular Mechanisms ◽  
Pyramidal Neurons ◽  
Field Potential ◽  
Pyramidal Cells ◽  
Anterior Cingulate ◽  
Mapping Technique ◽  
Synaptic Connections ◽  
Patch Clamp Recording ◽  
Brain Functions

AbstractThe ACC is an important brain area for the processing of pain-related information. Studies of synaptic connections within the ACC provide an understanding of basic cellular and molecular mechanisms for brain functions such as pain, emotion and related cognitive functions. Previous study of ACC synaptic transmission mainly focused on presumably thalamic inputs into pyramidal cells. In the present study, we developed a new mapping technique by combining single neuron whole-cell patch-clamp recording with 64 multi-channel field potential recording (MED64) to examine the properties of excitatory inputs into a single neuron in the ACC. We found that a single patched pyramidal neuron or interneuron simultaneously received heterogeneous excitatory synaptic innervations from different subregions (ventral, dorsal, deep, and superficial layers) in the ACC. Conduction velocity is faster as stimulation distance increases in pyramidal neurons. Fast-spiking interneurons (FS-IN) show slower inactivation when compared to pyramidal neurons and regular-spiking interneurons (RS-IN) while pyramidal neurons displayed the most rapid activation. Bath application of non-competitive AMPA receptor antagonist GYKI 53655 followed by CNQX revealed that both FS-INs and RS-INs have AMPA and KA mediated components. Our studies provide a new strategy and technique for studying the network of synaptic connections.

Advances in the study of the mechanochemical coupling of kinesin

2018 ◽  
Vol 32 (18) ◽  
pp. 1840001 ◽  
Author(s):  
Ming Li ◽  
Zhong-Can Ou-Yang ◽  
Yao-Gen Shu
Keyword(s):  
Molecular Dynamics ◽  
Single Molecule ◽  
Intracellular Transport ◽  
Coordination Mechanism ◽  
Personal Perspective ◽  
Long Distance ◽  
Future Studies ◽  
Mechanochemical Coupling ◽  
Dynamics Simulations ◽  
Made In

Kinesin is a two-headed linear motor for intracellular transport. It can walk a long distance in a hand-over-hand manner along the track before detaching (i.e., high processivity), and it consumes one ATP molecule for each step (i.e., tight mechanochemical coupling). The mechanisms of the coordination of its two heads and the mechanochemical coupling are the central issues of numerous researches. A few advances have been made in recent decades, thanks to the development of single-molecule technologies and molecular dynamics simulations. In this paper, we review some progress of the studies on the kinematics, energetics, coordination mechanism, mechanochemical mechanism of kinesin. We also present a personal perspective on the future studies of kinesin.

scholarly journals Dynamic Interaction of Norfloxacin to Magnesium Monitored by Bacterial Outer Membrane Nanopores

2020 ◽  
Author(s):  
Jiajun Wang ◽  
Jigneshkumar Dahyabhai Prajapati ◽  
Ulrich Kleinekathöfer ◽  
Mathias Winterhalter
Keyword(s):  
Outer Membrane ◽  
Lipid Bilayers ◽  
Brownian Dynamics ◽  
Single Channel ◽  
Ion Selectivity ◽  
Computational Modelling ◽  
Free Energy Calculations ◽  
Divalent Ions ◽  
Dynamics Simulations ◽  
Brownian Dynamics Simulations

The effect of divalent ions on the permeability of norfloxacin across the major outer membrane channels from <i>E. coli</i> (OmpF, OmpC) and <i>E. aerogenes</i> (Omp35, Omp36) has been investigated at the single channel level. To understand the rate limiting steps in permeation, we reconstituted single porin into planar lipid bilayers and analyzed the ion current fluctuations caused in the presence of norfloxacin. To obtain an atomistic view, we complemented the experiments with millisecond-long free energy calculations based on temperature-accelerated Brownian dynamics simulations to identify the most probable permeation pathways of the antibiotics through the respective pore. Both, experimental analysis and computational modelling, suggest that norfloxacin is able to permeate through the larger porins, i.e., OmpF, OmpC, and Omp35, whereas it only binds to the slightly narrower porin Omp36. Moreover, divalent ions can bind to negatively charged residues inside the porin, reversing the ion selectivity of the pore. In addition, the divalent ions can chelate with the fluoroquinolones and alter their physicochemical properties. The results suggest that the conjugation must break with either one of them when the antibiotics molecules bypass the lumen of the porin, with the conjugation to the antibiotic being more stable than that to the pore. In general, the permeation or binding process of fluoroquinolone in porins occurs irrespective of the presence of divalent ions, but the presences of divalent ions can vary the kinetics significantly.

scholarly journals Connectivity and network state-dependent recruitment of long-range VIP-GABAergic neurons in the mouse hippocampus

2018 ◽  
Author(s):  
Ruggiero Francavilla ◽  
Vincent Villette ◽  
Xiao Luo ◽  
Simon Chamberland ◽  
Einer Muñoz-Pino ◽  
...  
Keyword(s):  
Molecular Diversity ◽  
Pyramidal Cells ◽  
Functional Specialization ◽  
Gabaergic Interneurons ◽  
Long Distance ◽  
State Dependent ◽  
Mouse Hippocampus ◽  
Ca1 Area ◽  
New Evidence

AbstractGABAergic interneurons in the hippocampus provide for local and long-distance coordination of neurons in functionally connected areas. Vasoactive intestinal peptide-expressing (VIP+) interneurons occupy a distinct niche in circuitry as many of them specialize in innervating GABAergic cells, thus providing network disinhibition. In the CA1 hippocampus, VIP+ interneuron-selective cells target local interneurons. Here, we discovered a novel type of VIP+ neuron whose axon innervates CA1 and also projects to the subiculum (VIP-LRPs). VIP-LRPs showed specific molecular properties and targeted interneurons within the CA1 area but both interneurons and pyramidal cells within subiculum. They were interconnected through gap junctions but demonstrated sparse spike coupling in vitro. In awake mice, VIP-LRPs decreased their activity during theta-run epochs and were more active during quiet wakefulness but not coupled to sharp-wave ripples. Together, the data provide new evidence for VIP interneuron molecular diversity and functional specialization in controlling cell ensembles along the hippocampo-subicular axis.

scholarly journals Ion-water coupling controls class A GPCR signal transduction pathways

2020 ◽  
Author(s):  
Neil J. Thomson ◽  
Owen N. Vickery ◽  
Callum M. Ives ◽  
Ulrich Zachariae
Keyword(s):  
Binding Site ◽  
G Protein ◽  
Signal Transmission ◽  
Water Molecules ◽  
Long Distance ◽  
Protein Binding Region ◽  
Dynamics Simulations ◽  
Key Residues ◽  
Extracellular Sodium ◽  
Communication Pathway

G-protein-coupled receptors (GPCRs) transmit signals across the cell membrane, forming the largest family of membrane proteins in humans. Most GPCRs activate through an evolutionarily conserved mechanism, which involves reorientation of helices and key residues, rearrangement of a hydrogen bonding network mediated by water molecules, and the expulsion of a sodium ion from a protonatable binding site. However, how these components interplay to engage the signal effector binding site remains elusive. Here, we applied information theory to molecular dynamics simulations of pharmaceutically important GPCRs to trace concerted conformational variations across the receptors. We discovered a conserved communication pathway that includes protein residues and cofactors and enables the exchange of information between the extracellular sodium binding site and the intracellular G-protein binding region, coupling the most highly conserved protonatable residues at long distance. Reorientation of internal water molecules was found to be essential for signal transmission along this pathway. By inhibiting protonation, sodium decoupled this connectivity, identifying the ion as a master switch that determines the receptors’ ability to move towards active conformations.

scholarly journals Role of allosteric switches and adaptor domains in long-distance cross-talk and transient tunnel formation

2020 ◽  
Vol 6 (14) ◽  
pp. eaay7919
Author(s):  
Nandini Sharma ◽  
Navjeet Ahalawat ◽  
Padmani Sandhu ◽  
Erick Strauss ◽  
Jagannath Mondal ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Active Sites ◽  
Long Distance ◽  
Dynamic Interactions ◽  
Interface Control ◽  
Protein Energy ◽  
Catalytic Loop ◽  
Ammonia Tunnel ◽  
Dynamics Simulations

Transient tunnels that assemble and disassemble to facilitate passage of unstable intermediates in enzymes containing multiple reaction centers are controlled by allosteric cues. Using the 140-kDa purine biosynthetic enzyme PurL as a model system and a combination of biochemical and x-ray crystallographic studies, we show that long-distance communication between ~25-Å distal active sites is initiated by an allosteric switch, residing in a conserved catalytic loop, adjacent to the synthetase active site. Further, combinatory experiments seeded from molecular dynamics simulations help to delineate transient states that bring out the central role of nonfunctional adaptor domains. We show that carefully orchestrated conformational changes, facilitated by interplay of dynamic interactions at the allosteric switch and adaptor-domain interface, control reactivity and concomitant formation of the ammonia tunnel. This study asserts that substrate channeling is modulated by allosteric hotspots that alter protein energy landscape, thereby allowing the protein to adopt transient conformations paramount to function.

Numerical Procedure for Non-Hertzian Wheel-Rail Contact Model Integrated in Quasi-Steady Railway Vehicle Motion Solver

2020 ◽  
Author(s):  
Takayuki Tanaka ◽  
Hiroyuki Sugiyama
Keyword(s):  
Vehicle Dynamics ◽  
Numerical Procedure ◽  
Contact Model ◽  
Hertzian Contact ◽  
Railway Vehicle ◽  
Long Distance ◽  
Elliptical Contact ◽  
Vehicle Motion ◽  
Contact Shape ◽  
Dynamics Simulations

Abstract Although the Hertzian contact theory is widely utilized in railway vehicle simulations with new wheel and rail profiles, the Hertzian contact assumptions would lead to inaccurate contact prediction for severely worn wheel and rail profiles due to their geometric conformity, causing non-elliptical contact shapes as well as pressure distribution. For this reason, various non-Hertzian contact models have been studied for use in vehicle dynamics simulations. Among others, a method proposed by Piotrowski and Kik has gained acceptance in predicting non-elliptical wheel-rail contact for vehicle dynamics simulations. Despite the elegant formulation and its accuracy, detailed online geometric calculation for non-elliptical contact shape is required for all the contact patches at every iteration, along with iterative evaluation of the force-deflection relationship. It leads to computation burdens for use in long-distance vehicle simulations. Therefore, in this study, an off-line based numerical procedure for non-Hertzian contact model is developed and integrated in the quasi-steady railway vehicle motion solver.

Hippocampal Interneurons Are Excited Via Serotonin-Gated Ion Channels

1997 ◽  
Vol 78 (5) ◽  
pp. 2493-2502 ◽  
Author(s):  
Lori L. McMahon ◽  
Julie A. Kauer
Keyword(s):  
Ion Channels ◽  
Synaptic Transmission ◽  
Dentate Gyrus ◽  
Granule Cells ◽  
Brain Slices ◽  
Pyramidal Cells ◽  
Stratum Radiatum ◽  
Negative Slope ◽  
Patch Clamp Recording ◽  
Gated Ion Channels

McMahon, Lori L. and Julie A. Kauer. Hippocampal interneurons are excited via serotonin-gated ion channels. J. Neurophysiol. 78: 2493–2502, 1997. Serotonergic neurons of the median raphe nucleus heavily innervate hippocampal GABAergic interneurons located in stratum radiatum of area CA1, suggesting that this strong subcortical projection may modulate interneuron excitability. Using whole cell patch-clamp recording from interneurons in brain slices, we tested the effects of serotonin (5-HT) on the physiological properties of these interneurons. Serotonin produces a rapid inward current that persists when synaptic transmission is blocked by tetrodotoxin and cobalt, and is unaffected by ionotropic glutamate and γ-aminobutyric acid (GABA) receptor antagonists. The 5-HT–induced current was independent of G-protein activation. Pharmacological evidence indicates that 5-HT directly excites these interneurons through activation of 5-HT3 receptors. At membrane potentials negative to −55 mV, the current-voltage ( I-V) relationship of the 5-HT current displays a region of negative slope conductance. Therefore the response of interneurons to 5-HT strongly depends on membrane potential and increases greatly as cells are depolarized. Removal of extracellular calcium, but not magnesium, increases the amplitude of 5-HT–induced currents and removes the region of negative slope conductance, thereby linearizing the I-V relationship. The axons of 5-HT–responsive interneurons ramify widely within CA1; some of these interneurons also project to and arborize extensively in the dentate gyrus. The organization of these inhibitory connections strongly suggests that these cells regulate excitability of both CA1 pyramidal cells and dentate granule cells. As our results indicate that 5-HT may mediate fast excitatory synaptic transmission onto these interneurons, serotonergic inputs can simultaneously modulate the output of both hippocampus and dentate gyrus.

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