scholarly journals Astrocytic regulation of synchronous bursting in cortical cultures: from local to global

2019 ◽  
Author(s):  
Ravi Kumar ◽  
Yu-Ting Huang ◽  
Chun-Chung Chen ◽  
Shun-Fen Tzeng ◽  
C. K. Chan
Keyword(s):  
Negative Feedback ◽  
Neuronal Networks ◽  
Glutamate Uptake ◽  
Electrode Array ◽  
Underlying Mechanism ◽  
Neuronal Firing ◽  
Common Belief ◽  
Tripartite Synapse ◽  
Detailed Simulation ◽  
Long Time

AbstractSynchronous bursting (SB) is ubiquitous in neuronal networks. It is known for a long time that SB is driven by glutamatergic neurotransmissions but its underlying mechanism is still unclear. Recent studies show that local glutamate recycle by astrocytes can affect neuronal activities nearby. Since SB is independent of network structure, it is conceivable that the local dynamics might also be the origin of SB in networks. We investigated the effects of local glutamate dynamics on SBs in both cultures developed on multi-electrode array (MEA) systems and a tripartite synapse simulation model. In our experiments, local glutamate recycle dynamics are studied by pharmacologically targeting the astrocytic glutamate transporters (GLT-1), while neuronal firing activities and synaptic glutamate level are simultaneously monitored with MEA and glutamate sensor (iGluSnFR) expressed on surface of astrocytes respectively. We found SBs to be synchronized with glutamate transients and the manipulation of local glutamate dynamics can indeed alter the global properties of the SBs. Detailed simulation of a network with astrocytic glutamate uptake and recycle mechanisms conforming with the experimental observations revealed that astrocytes function as a slow negative feedback for the neuronal activities in the network. With this model, SB can be understood as the alternation between the positive and negative feedback in the neurons and astrocytes in the network respectively. An understanding of this glutamate trafficking dynamics is of general application to explain disordered phenomena in neuronal systems, and therefore can provide new insights into the origin of fatal seizure-like behavior.SignificanceSynchronous bursting (SB) is a hallmark of neuronal circuits. Contrary to the common belief that the SB is governed mainly by neuron-neuron interactions, this study shows that SBs are orchestrated through a generic neuron-astrocyte tripartite interactions. These interactions, identified as glutamate uptake and recycle processes in astrocytes, control the excitability of neuronal networks and shape the overall SB patterns. Our simulation results suggest that astrocytes traffic more glutamate than neurons and actively regulating glutamate proceedings around synapses. A bipartite synapse is a good approximation of a tripartite synapse provided that astrocyte-dependent glutamate content is taken into account. Our findings provide key insights into the ubiquity of SB and the origin of fatal seizure-like behavior in brain arising from astrocytic malfunction.

scholarly journals Astrocytic Regulation of Synchronous Bursting in Cortical Cultures: From Local to Global

2020 ◽  
Vol 1 (1) ◽  
Author(s):  
Ravi Kumar ◽  
Yu-Ting Huang ◽  
Chun-Chung Chen ◽  
Shun-Fen Tzeng ◽  
Chi-Keung Chan
Keyword(s):  
Negative Feedback ◽  
Glutamate Uptake ◽  
Underlying Mechanism ◽  
Neuronal Firing ◽  
Multielectrode Array ◽  
Fluorescent Reporter ◽  
General Application ◽  
Detailed Simulation ◽  
Positive And Negative Feedback ◽  
Neuronal Systems

Abstract Synchronous bursting (SB) is ubiquitous in neuronal networks and independent of network structure. Although it is known to be driven by glutamatergic neurotransmissions, its underlying mechanism remains unclear. Recent studies show that local glutamate recycle by astrocytes affects nearby neuronal activities, which indicate that the local dynamics might also be the origin of SBs in networks. We investigated the effects of local glutamate dynamics on SBs in both cultures developed on multielectrode array (MEA) systems and a tripartite synapse simulation. Local glutamate uptake by astrocytes was altered by pharmacological targeting of GLT-1 glutamate transporters, whereas neuronal firing activities and synaptic glutamate level was simultaneously monitored with MEA and astrocyte-specific glutamate sensors (intensity-based glutamate-sensing fluorescent reporter), respectively. Global SB properties were significantly altered on targeting GLT-1. Detailed simulation of a network with astrocytic glutamate uptake and recycle mechanisms, conforming with the experimental observations, shows that astrocytes function as a slow negative feedback to neuronal activities in the network. SB in the network can be realized as an alternation between positive and negative feedback in the neurons and astrocytes, respectively. An understanding of glutamate trafficking dynamics is of general application to explain how astrocyte malfunction can result in pathological seizure-like phenomena in neuronal systems.

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.

scholarly journals The Ocular Surface and the Coronavirus Disease 2019: Does a Dual ‘Ocular Route’ Exist?

2020 ◽  
Vol 9 (5) ◽  
pp. 1269 ◽  
Author(s):  
Pietro Emanuele Napoli ◽  
Matteo Nioi ◽  
Ernesto d’Aloja ◽  
Maurizio Fossarello
Keyword(s):  
Ocular Surface ◽  
Tear Film ◽  
Underlying Mechanism ◽  
Point Of View ◽  
World Health ◽  
Surface System ◽  
Important Health ◽  
Long Time ◽  
The Moment ◽  
Health Organization

Coronavirus disease 2019 (COVID-19) is an important health problem that was defined as a pandemic by the World Health Organization on 11 March 2020. Although great concern has been expressed about COVID-19 infection acquired through ocular transmission, its underlying mechanism has not currently been clarified. In the current work, we analyzed and elucidated the two main elements that should be taken into account to understand the “ocular route”, both from a clinical and molecular point of view. They are represented by the dynamism of the ocular surface system (e.g., the tear film turnover) and the distribution of ACE2 receptors and TMPRSS2 protein. Although it seems, at the moment, that there is a low risk of coronavirus spreading through tears, it may survive for a long time or replicate in the conjunctiva, even in absence of conjunctivitis signs, indicating that eye protection (e.g., protective goggles alone or in association with face shield) is advisable to prevent contamination from external droplets and aerosol.

scholarly journals L-type voltage-gated calcium channel regulation of in vitro human cortical neuronal networks

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
William Plumbly ◽  
Nick Brandon ◽  
Tarek Z. Deeb ◽  
Jeremy Hall ◽  
Adrian J. Harwood
Keyword(s):  
Calcium Channel ◽  
Neuronal Networks ◽  
Gene Mutations ◽  
Synaptic Function ◽  
Neuronal Firing ◽  
Network Activity ◽  
Electrode Arrays ◽  
Voltage Gated ◽  
Voltage Gated Calcium Channel

Abstract The combination of in vitro multi-electrode arrays (MEAs) and the neuronal differentiation of stem cells offers the capability to study human neuronal networks from patient or engineered human cell lines. Here, we use MEA-based assays to probe synaptic function and network interactions of hiPSC-derived neurons. Neuronal network behaviour first emerges at approximately 30 days of culture and is driven by glutamate neurotransmission. Over a further 30 days, inhibitory GABAergic signalling shapes network behaviour into a synchronous regular pattern of burst firing activity and low activity periods. Gene mutations in L-type voltage gated calcium channel subunit genes are strongly implicated as genetic risk factors for the development of schizophrenia and bipolar disorder. We find that, although basal neuronal firing rate is unaffected, there is a dose-dependent effect of L-type voltage gated calcium channel inhibitors on synchronous firing patterns of our hiPSC-derived neural networks. This demonstrates that MEA assays have sufficient sensitivity to detect changes in patterns of neuronal interaction that may arise from hypo-function of psychiatric risk genes. Our study highlights the utility of in vitro MEA based platforms for the study of hiPSC neural network activity and their potential use in novel compound screening.

scholarly journals NLRX1 Enhances Glutamate Uptake and Inhibits Glutamate Release by Astrocytes

Cells ◽  
2019 ◽  
Vol 8 (5) ◽  
pp. 400 ◽  
Author(s):  
Shaimaa Mahmoud ◽  
Marjan Gharagozloo ◽  
Camille Simard ◽  
Abdelaziz Amrani ◽  
Denis Gris
Keyword(s):  
Glutamate Uptake ◽  
Glutamate Release ◽  
Neuronal Firing ◽  
Glutamate Excitotoxicity ◽  
Cns Inflammation ◽  
Atp Production ◽  
Inflammatory Conditions ◽  
Mitochondrial Functions ◽  
The Central Nervous System ◽  
First Time

Uptake of glutamate from the extracellular space and glutamate release to neurons are two major processes conducted by astrocytes in the central nervous system (CNS) that protect against glutamate excitotoxicity and strengthen neuronal firing, respectively. During inflammatory conditions in the CNS, astrocytes may lose one or both of these functions, resulting in accumulation of the extracellular glutamate, which eventually leads to excitotoxic neuronal death, which in turn worsens the CNS inflammation. NLRX1 is an innate immune NOD-like receptor that inhibits the major inflammatory pathways. It is localized in the mitochondria and was shown to inhibit cell death, enhance ATP production, and dampen oxidative stress. In the current work, using primary murine astrocyte cultures from WT and Nlrx1-/- mice, we demonstrate that NLRX1 potentiates astrocytic glutamate uptake by enhancing mitochondrial functions and the functional activity of glutamate transporters. Also, we report that NLRX1 inhibits glutamate release from astrocytes by repressing Ca2+-mediated glutamate exocytosis. Our study, for the first time, identified NLRX1 as a potential regulator of glutamate homeostasis in the CNS.

scholarly journals Intrinsically stretchable electrode array enabled in vivo electrophysiological mapping of atrial fibrillation at cellular resolution

2020 ◽  
Vol 117 (26) ◽  
pp. 14769-14778 ◽  
Author(s):  
Jia Liu ◽  
Xinyuan Zhang ◽  
Yuxin Liu ◽  
Miguel Rodrigo ◽  
Patrick D. Loftus ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Spatial Resolution ◽  
Electrode Array ◽  
Chronic Atrial Fibrillation ◽  
Underlying Mechanism ◽  
Cellular Level ◽  
Definitive Treatment ◽  
Comparable Efficacy ◽  
Signal Ratio

Electrophysiological mapping of chronic atrial fibrillation (AF) at high throughput and high resolution is critical for understanding its underlying mechanism and guiding definitive treatment such as cardiac ablation, but current electrophysiological tools are limited by either low spatial resolution or electromechanical uncoupling of the beating heart. To overcome this limitation, we herein introduce a scalable method for fabricating a tissue-like, high-density, fully elastic electrode (elastrode) array capable of achieving real-time, stable, cellular level-resolution electrophysiological mapping in vivo. Testing with acute rabbit and porcine models, the device is proven to have robust and intimate tissue coupling while maintaining its chemical, mechanical, and electrical properties during the cardiac cycle. The elastrode array records epicardial atrial signals with comparable efficacy to currently available endocardial-mapping techniques but with 2 times higher atrial-to-ventricular signal ratio and >100 times higher spatial resolution and can reliably identify electrical local heterogeneity within an area of simultaneously identified rotor-like electrical patterns in a porcine model of chronic AF.

scholarly journals Plasticity of Neuron-Glial Transmission: Equipping Glia for Long-Term Integration of Network Activity

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Wayne Croft ◽  
Katharine L. Dobson ◽  
Tomas C. Bellamy
Keyword(s):  
Long Term Potentiation ◽  
Brain Regions ◽  
Neuronal Firing ◽  
Network Activity ◽  
Neuronal Function ◽  
Term Potentiation ◽  
Bidirectional Communication ◽  
Long Time ◽  
Activity Dependent

The capacity of synaptic networks to express activity-dependent changes in strength and connectivity is essential for learning and memory processes. In recent years, glial cells (most notably astrocytes) have been recognized as active participants in the modulation of synaptic transmission and synaptic plasticity, implicating these electrically nonexcitable cells in information processing in the brain. While the concept of bidirectional communication between neurons and glia and the mechanisms by which gliotransmission can modulate neuronal function are well established, less attention has been focussed on the computational potential of neuron-glial transmission itself. In particular, whether neuron-glial transmission is itself subject to activity-dependent plasticity and what the computational properties of such plasticity might be has not been explored in detail. In this review, we summarize current examples of plasticity in neuron-glial transmission, in many brain regions and neurotransmitter pathways. We argue that induction of glial plasticity typically requires repetitive neuronal firing over long time periods (minutes-hours) rather than the short-lived, stereotyped trigger typical of canonical long-term potentiation. We speculate that this equips glia with a mechanism for monitoring average firing rates in the synaptic network, which is suited to the longer term roles proposed for astrocytes in neurophysiology.

scholarly journals Novel target identification using single cell sequencing and electrophysiology of cardiac sympathetic neurons in disease

2019 ◽  
Author(s):  
Harvey Davis ◽  
Neil Herring ◽  
David J Paterson
Keyword(s):  
Single Cell ◽  
Target Identification ◽  
Sodium Current ◽  
Sympathetic Neurons ◽  
Sympathetic Nerves ◽  
Underlying Mechanism ◽  
Neuronal Firing ◽  
Surgical Removal ◽  
Spontaneously Hypertensive ◽  
Stellate Ganglia

AbstractThe activity of cardiac sympathetic nerves from the stellate ganglia is increased in many cardiovascular diseases contributing to the pathophysiology, however the mechanisms underlying this are unknown. Moreover, clinical studies show their surgical removal is an effective treatment, despite the biophysical properties of these neurons being largely unstudied. Here we demonstrate that stellate ganglia neurons from prehypertensive spontaneously hypertensive rats are hyperactive and describe in detail their electrophysiological phenotype guided by single cell RNA-sequencing, molecular biology and perforated patch-clamp to uncover the underlying mechanism. The expression of key transcripts was confirmed in human stellate ganglia. We further demonstrate the contribution of a plethora of ion channels to stellate ganglia neuronal firing, and show that hyperexcitability was curbed by M-current activators, non-selective sodium current blockers or inhibition of Nav1.1-1.3, Nav1.6 or INaP. These findings have implications for target discovery to reduce cardiac sympathetic activity without resorting to surgery.

scholarly journals L-type voltage-gated calcium channel regulation of in vitro human cortical neuronal networks

2018 ◽  
Author(s):  
William Plumbly ◽  
Nicholas J. Brandon ◽  
Tarek Z. Deeb ◽  
Jeremy Hall ◽  
Adrian J. Harwood
Keyword(s):  
Calcium Channel ◽  
Neuronal Networks ◽  
Gene Mutations ◽  
Synaptic Function ◽  
Neuronal Firing ◽  
Network Activity ◽  
Electrode Arrays ◽  
Voltage Gated ◽  
Voltage Gated Calcium Channel

The combination of in vitro multi-electrode arrays (MEAs) and the neuronal differentiation of stem cells offers the capability to study human neuronal networks from patient or engineered human cell lines. Here, we use MEA-based assays to probe synaptic function and network interactions of hiPSC-derived neurons. Neuronal network behaviour first emerges at approximately 30 days of culture and is driven by glutamate neurotransmission. Over a further 30 days, inhibitory GABergic signalling shapes network behaviour into a synchronous regular pattern of burst firing activity and low activity periods. Gene mutations in L-type voltage gated calcium channel subunit genes are strongly implicated as genetic risk factors for the development of schizophrenia and bipolar disorder. We find that, although basal neuronal firing rate is unaffected, there is a dose-dependent effect of L-type voltage gated calcium channel inhibitors on synchronous firing patterns of our hiPSC-derived neural networks. This demonstrates that MEA assays have sufficient sensitivity to detect changes in patterns of neuronal interaction that may arise from hypo-function of psychiatric risk genes. Our study highlights the utility of in vitro MEA based platforms for the study of hiPSC neural network activity and their potential use in novel compound screening.

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