scholarly journals Active membrane conductances and morphology of a collision detection neuron broaden its impedance profile and improve membrane synchrony

2018 ◽  
Author(s):  
Richard Dewell ◽  
Fabrizio Gabbiani
Keyword(s):  
Synaptic Input ◽  
Collision Detection ◽  
Dendritic Morphology ◽  
Synaptic Integration ◽  
Neuronal Membrane ◽  
Hcn Channels ◽  
Movement Detector ◽  
Membrane Impedance ◽  
Wide Range

Brains processes information through the coordinated efforts of billions of individual neurons, each encoding a small part of the overall information stream. Central to this is how neurons integrate and transform complex patterns of synaptic inputs. The neuronal membrane impedance sets the gain and timing for synaptic integration, determining a neuron's ability to discriminate between synaptic input patterns. Using single and dual dendritic recordings in vivo, pharmacology, and computational modeling, we characterized the membrane impedance of a collision detection neuron in the grasshopper, Schistocerca americana. We examined how the cellular properties of the lobula giant movement detector (LGMD) neuron are tuned to enable the discrimination of synaptic input patterns key to its role in collision detection. We found that two common active conductances gH and gM, mediated respectively by hyperpolarization-activated cyclic nucleotide gated (HCN) channels and by muscarine sensitive M-type K+ channels, promote broadband integration with high temporal precision over the LGMD's natural range of membrane potentials and synaptic input frequencies. Additionally, we found that the LGMD's branching morphology increased the gain and decreased delays associated with the mapping of synaptic input currents to membrane potential. We investigated whether other branching dendritic morphologies fulfill a similar function and found this to be true for a wide range of morphologies, including those of neocortical pyramidal neurons and cerebellar Purkinje cells. These findings further our understanding of the integration properties of individual neurons by showing the unexpected role played by two widespread active conductances and by dendritic morphology in shaping synaptic integration.

scholarly journals Active membrane conductances and morphology of a collision detection neuron broaden its impedance profile and improve discrimination of input synchrony

2019 ◽  
Vol 122 (2) ◽  
pp. 691-706 ◽  
Author(s):  
Richard B. Dewell ◽  
Fabrizio Gabbiani
Keyword(s):  
Synaptic Input ◽  
Collision Detection ◽  
Model Neuron ◽  
Dendritic Morphology ◽  
Membrane Potentials ◽  
Neuronal Membrane ◽  
Hcn Channels ◽  
Movement Detector ◽  
Membrane Impedance ◽  
Wide Range

How neurons filter and integrate their complex patterns of synaptic inputs is central to their role in neural information processing. Synaptic filtering and integration are shaped by the frequency-dependent neuronal membrane impedance. Using single and dual dendritic recordings in vivo, pharmacology, and computational modeling, we characterized the membrane impedance of a collision detection neuron in the grasshopper Schistocerca americana. This neuron, the lobula giant movement detector (LGMD), exhibits consistent impedance properties across frequencies and membrane potentials. Two common active conductances gH and gM, mediated respectively by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and by muscarine-sensitive M-type K+ channels, promote broadband integration with high temporal precision over the LGMD’s natural range of membrane potentials and synaptic input frequencies. Additionally, we found that a model based on the LGMD’s branching morphology increased the gain and decreased the delay associated with the mapping of synaptic input currents to membrane potential. More generally, this was true for a wide range of model neuron morphologies, including those of neocortical pyramidal neurons and cerebellar Purkinje cells. These findings show the unexpected role played by two widespread active conductances and by dendritic morphology in shaping synaptic integration. NEW & NOTEWORTHY Neuronal filtering and integration of synaptic input patterns depend on the electrochemical properties of dendrites. We used an identified collision detection neuron in grasshoppers to examine how its morphology and two conductances affect its membrane impedance in relation to the computations it performs. The neuronal properties examined are ubiquitous and therefore promote a general understanding of neuronal computations, including those in the human brain.

scholarly journals Extraction of Synaptic Input Properties in Vivo

2017 ◽  
Vol 29 (7) ◽  
pp. 1745-1768 ◽  
Author(s):  
Paolo Puggioni ◽  
Marta Jelitai ◽  
Ian Duguid ◽  
Mark C.W. van Rossum
Keyword(s):  
Voltage Clamp ◽  
Synaptic Input ◽  
Event Rate ◽  
Synaptic Integration ◽  
Neural Function ◽  
State Change ◽  
Input Rate ◽  
Time Constants ◽  
Synaptic Inputs

Knowledge of synaptic input is crucial for understanding synaptic integration and ultimately neural function. However, in vivo, the rates at which synaptic inputs arrive are high, so that it is typically impossible to detect single events. We show here that it is nevertheless possible to extract the properties of the events and, in particular, to extract the event rate, the synaptic time constants, and the properties of the event size distribution from in vivo voltage-clamp recordings. Applied to cerebellar interneurons, our method reveals that the synaptic input rate increases from 600 Hz during rest to 1000 Hz during locomotion, while the amplitude and shape of the synaptic events are unaffected by this state change. This method thus complements existing methods to measure neural function in vivo.

scholarly journals M-current regulates firing mode and spike reliability in a collision detecting neuron

2018 ◽  
Author(s):  
Richard B. Dewell ◽  
Fabrizio Gabbiani
Keyword(s):  
Computational Modeling ◽  
Collision Detection ◽  
Compound Eye ◽  
Spike Timing ◽  
Burst Firing ◽  
False Alarms ◽  
Movement Detector ◽  
M Current ◽  
Firing Mode

AbstractAll animals must detect impending collisions to escape them, and they must reliably discriminate them from non-threatening stimuli to prevent false alarms. Therefore, it is no surprise that animals have evolved highly selective and sensitive neurons dedicated to such tasks. We examined a well-studied collision detection neuron in the grasshopper Schistocerca americana using in vivo electrophysiology, pharmacology, and computational modeling. This lobula giant movement detector (LGMD) neuron is excitable by inputs originating from each ommatidia of the compound eye, and it has many intrinsic properties that increase its selectivity to objects approaching on a collision course, including switching between burst and non-burst firing. Here, we demonstrate that the LGMD neuron exhibits a large M current, generated by non-inactivating K+ channels, that narrows the window of dendritic integration, regulates a firing mode switch between burst and isolated spiking, increases the precision of spike timing, and increases the reliability of spike propagation to downstream motor centers. By revealing how the M current increases the LGMD’s ability to detect impending collisions our results suggest that it may play an analogous role in other collision detection circuits.New & NoteworthyThe ability to reliably detect impending collisions is a critical survival skill. The nervous systems of many animals have developed dedicated neurons for accomplishing this task. We used a mix of in vivo electrophysiology and computational modeling to investigate the role of M potassium channels within one such collision detecting neuron and showed that through regulation of burst firing and increasing spiking reliability the M current increases the ability to detect impending collisions.

scholarly journals M current regulates firing mode and spike reliability in a collision-detecting neuron

2018 ◽  
Vol 120 (4) ◽  
pp. 1753-1764 ◽  
Author(s):  
Richard B. Dewell ◽  
Fabrizio Gabbiani
Keyword(s):  
Computational Modeling ◽  
Collision Detection ◽  
Compound Eye ◽  
Spike Timing ◽  
False Alarms ◽  
Movement Detector ◽  
In Vivo Electrophysiology ◽  
M Current ◽  
Firing Mode

All animals must detect impending collisions to escape and reliably discriminate them from nonthreatening stimuli, thus preventing false alarms. Therefore, it is no surprise that animals have evolved highly selective and sensitive neurons dedicated to such tasks. We examined a well-studied collision-detection neuron in the grasshopper ( Schistocerca americana) using in vivo electrophysiology, pharmacology, and computational modeling. This lobula giant movement detector (LGMD) neuron is excitable by inputs originating from each ommatidia of the compound eye. It possesses many intrinsic properties that increase its selectivity to objects approaching on a collision course, including switching between burst and nonburst firing. In this study, we demonstrate that the LGMD neuron exhibits a large M current, generated by noninactivating K+ channels, that shortens the temporal window of dendritic integration, regulates a firing mode switch between burst and isolated spiking, increases the precision of spike timing, and increases the reliability of spike propagation to downstream motor centers. By revealing how the M current increases the LGMD’s ability to detect impending collisions, our results suggest that similar channels may play an analogous role in other collision detection circuits. NEW & NOTEWORTHY The ability to reliably detect impending collisions is a critical survival skill. The nervous systems of many animals have developed dedicated neurons for accomplishing this task. We used a mix of in vivo electrophysiology and computational modeling to investigate the role of M potassium channels within one such collision-detecting neuron and show that through regulation of burst firing and enhancement of spiking reliability, the M current increases the ability to detect impending collisions.

Evaluation of 99mTc-Label led Vitamin K4 as an Agent for Testicular Imaging

1991 ◽  
Vol 30 (01) ◽  
pp. 35-39 ◽  
Author(s):  
H. S. Durak ◽  
M. Kitapgi ◽  
B. E. Caner ◽  
R. Senekowitsch ◽  
M. T. Ercan
Keyword(s):  
Soft Tissue ◽  
Room Temperature ◽  
Normal Subjects ◽  
Left Testis ◽  
Wide Range ◽  
Activity Ratios ◽  
The Right ◽  
Radioactivity Levels

Vitamin K4 was labelled with 99mTc with an efficiency higher than 97%. The compound was stable up to 24 h at room temperature, and its biodistribution in NMRI mice indicated its in vivo stability. Blood radioactivity levels were high over a wide range. 10% of the injected activity remained in blood after 24 h. Excretion was mostly via kidneys. Only the liver and kidneys concentrated appreciable amounts of radioactivity. Testis/soft tissue ratios were 1.4 and 1.57 at 6 and 24 h, respectively. Testis/blood ratios were lower than 1. In vitro studies with mouse blood indicated that 33.9 ±9.6% of the radioactivity was associated with RBCs; it was washed out almost completely with saline. Protein binding was 28.7 ±6.3% as determined by TCA precipitation. Blood clearance of 99mTc-l<4 in normal subjects showed a slow decrease of radioactivity, reaching a plateau after 16 h at 20% of the injected activity. In scintigraphic images in men the testes could be well visualized. The right/left testis ratio was 1.08 ±0.13. Testis/soft tissue and testis/blood activity ratios were highest at 3 h. These ratios were higher than those obtained with pertechnetate at 20 min post injection.99mTc-l<4 appears to be a promising radiopharmaceutical for the scintigraphic visualization of testes.

Ethnomedicinal uses, Phytochemistry and Pharmacological Aspects of the Genus Berberis Linn: A Comprehensive Review

2020 ◽  
Vol 23 ◽  
Author(s):  
Roohi Mohi-ud-din ◽  
Reyaz Hassan Mir ◽  
Prince Ahad Mir ◽  
Saeema Farooq ◽  
Syed Naiem Raza ◽  
...  
Keyword(s):  
Chemical Constituents ◽  
Pharmacological Activities ◽  
Traditional Use ◽  
Comprehensive Review ◽  
Wide Range ◽  
Anti Cancer ◽  
Comprehensive Survey ◽  
Ethnomedicinal Uses

Background: Genus Berberis (family Berberidaceae), which contains about 650 species and 17 genera worldwide, has been used in folklore and various traditional medicine systems. Berberis Linn. is the most established group among genera with around 450-500 species across the world. This comprehensive review will not only help researchers for further evaluation but also provide substantial information for future exploitation of species to develop novel herbal formulations. Objective: The present review is focussed to summarize and collect the updated review of information of Genus Berberis species reported to date regarding their ethnomedicinal information, chemical constituents, traditional/folklore use, and reported pharmacological activities on more than 40 species of Berberis. Conclusion: A comprehensive survey of the literature reveals that various species of the genus possess various phytoconstituents mainly alkaloids, flavonoid based compounds isolated from different parts of a plant with a wide range of pharmacological activities. So far, many pharmacological activities like anti-cancer, anti-hyperlipidemic, hepatoprotective, immunomodulatory, anti-inflammatory both in vitro & in vivo and clinical study of different extracts/isolated compounds of different species of Berberis have been reported, proving their importance as a medicinal plant and claiming their traditional use.

Current Status and Future Perspective for Research on Medicinal Plants with Anticancerous Activity and Minimum Cytotoxic Value

2019 ◽  
Vol 20 (12) ◽  
pp. 1227-1243
Author(s):  
Hina Qamar ◽  
Sumbul Rehman ◽  
D.K. Chauhan
Keyword(s):  
Side Effects ◽  
Medicinal Plants ◽  
Anticancer Agents ◽  
Drug Targets ◽  
Psidium Guajava ◽  
Current Status ◽  
Future Perspective ◽  
Wide Range

Cancer is the second leading cause of morbidity and mortality worldwide. Although chemotherapy and radiotherapy enhance the survival rate of cancerous patients but they have several acute toxic effects. Therefore, there is a need to search for new anticancer agents having better efficacy and lesser side effects. In this regard, herbal treatment is found to be a safe method for treating and preventing cancer. Here, an attempt has been made to screen some less explored medicinal plants like Ammania baccifera, Asclepias curassavica, Azadarichta indica, Butea monosperma, Croton tiglium, Hedera nepalensis, Jatropha curcas, Momordica charantia, Moringa oleifera, Psidium guajava, etc. having potent anticancer activity with minimum cytotoxic value (IC50 >3μM) and lesser or negligible toxicity. They are rich in active phytochemicals with a wide range of drug targets. In this study, these medicinal plants were evaluated for dose-dependent cytotoxicological studies via in vitro MTT assay and in vivo tumor models along with some more plants which are reported to have IC50 value in the range of 0.019-0.528 mg/ml. The findings indicate that these plants inhibit tumor growth by their antiproliferative, pro-apoptotic, anti-metastatic and anti-angiogenic molecular targets. They are widely used because of their easy availability, affordable price and having no or sometimes minimal side effects. This review provides a baseline for the discovery of anticancer drugs from medicinal plants having minimum cytotoxic value with minimal side effects and establishment of their analogues for the welfare of mankind.

Approach in improving potency and selectivity of kinase inhibitors: Allosteric kinase inhibitors

2020 ◽  
Vol 21 ◽  
Author(s):  
Shangfei Wei ◽  
Tianming Zhao ◽  
Jie Wang ◽  
Xin Zhai
Keyword(s):  
Protein Interactions ◽  
Kinase Inhibitors ◽  
Binding Modes ◽  
Allosteric Inhibitors ◽  
Wide Range ◽  
Allosteric Sites ◽  
Protein Functions ◽  
Regulate Protein

: Allostery is an efficient and particular regulatory mechanism to regulate protein functions. Different from conserved orthosteric sites, allosteric sites have distinctive functional mechanism to form the complex regulatory network. In drug discovery, kinase inhibitors targeting the allosteric pockets have received extensive attention for the advantages of high selectivity and low toxicity. The approval of trametinib as the first allosteric inhibitor validated that allosteric inhibitors could be used as effective therapeutic drugs for treatment of diseases. To date, a wide range of allosteric inhibitors have been identified. In this perspective, we outline different binding modes and potential advantages of allosteric inhibitors. In the meantime, the research processes of typical and novel allosteric inhibitors are described briefly in terms of structureactivity relationships, ligand-protein interactions and in vitro and in vivo activity. Additionally, challenges as well as opportunities are presented.

In Silico Assessment of ADME Properties: Advances in Caco-2 Cell Monolayer Permeability Modeling

2019 ◽  
Vol 18 (26) ◽  
pp. 2209-2229 ◽  
Author(s):  
Hai Pham-The ◽  
Miguel Á. Cabrera-Pérez ◽  
Nguyen-Hai Nam ◽  
Juan A. Castillo-Garit ◽  
Bakhtiyor Rasulev ◽  
...  
Keyword(s):  
Intestinal Absorption ◽  
In Silico ◽  
Review Paper ◽  
Cell Monolayer ◽  
Cell Permeability ◽  
Drug Substances ◽  
Wide Range ◽  
Modeling Techniques

One of the main goals of in silico Caco-2 cell permeability models is to identify those drug substances with high intestinal absorption in human (HIA). For more than a decade, several in silico Caco-2 models have been made, applying a wide range of modeling techniques; nevertheless, their capacity for intestinal absorption extrapolation is still doubtful. There are three main problems related to the modest capacity of obtained models, including the existence of inter- and/or intra-laboratory variability of recollected data, the influence of the metabolism mechanism, and the inconsistent in vitro-in vivo correlation (IVIVC) of Caco-2 cell permeability. This review paper intends to sum up the recent advances and limitations of current modeling approaches, and revealed some possible solutions to improve the applicability of in silico Caco-2 permeability models for absorption property profiling, taking into account the above-mentioned issues.

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