A Multimodal Fitting Approach to Construct Single-Neuron Models with Patch Clamp and High-Density Microelectrode Arrays.

In computational neuroscience, multicompartment models are among the most biophysically realistic representations of single neurons. Constructing such models usually involves the use of the patch-clamp technique to record somatic voltage signals under different experimental conditions. The experimental data are then used to fit the many parameters of the model. While patching of the soma is currently the gold-standard approach to build multicompartment models, several studies have also evidenced a richness of dynamics in dendritic and axonal sections. Recording from the soma alone makes it hard to observe and correctly parameterize the activity of nonsomatic compartments. In order to provide a richer set of data as input to multicompartment models, we here investigate the combination of somatic patch-clamp recordings with recordings of high-density microelectrode arrays (HD-MEAs). HD-MEAs enable the observation of extracellular potentials and neural activity of neuronal compartments at subcellular resolution. In this work, we introduce a novel framework to combine patch-clamp and HD-MEA data to construct multicompartment models. We first validate our method on a ground-truth model with known parameters and show that the use of features extracted from extracellular signals, in addition to intracellular ones, yields models enabling better fits than using intracellular features alone. We also demonstrate our procedure using experimental data by constructing cell models from in vitro cell cultures. The proposed multimodal fitting procedure has the potential to augment the modeling efforts of the computational neuroscience community and provide the field with neuronal models that are more realistic and can be better validated.

Respiratory rhythm modulates membrane potential and spiking of nonolfactory neurons.

In recent years, several studies have shown a respiratory drive of the local field potential (LFP) in numerous brain areas so that the respiratory rhythm could be considered as a master clock promoting communication between distant brain locations. However, outside of the olfactory system, it remains unknown whether the respiratory rhythm could shape membrane potential (MP) oscillations. To fill this gap, we co-recorded MP and LFP activities in different nonolfactory brain areas, medial prefrontal cortex (mPFC), primary somatosensory cortex (S1), primary visual cortex (V1), and hippocampus (HPC), in urethane-anesthetized rats. Using respiratory cycle-by-cycle analysis, we observed that respiration could modulate both MP and spiking discharges in all recorded areas during episodes that we called respiration-related oscillations (RRo). Further quantifications revealed that RRo episodes were transient in most neurons (5 consecutive respiratory cycles in average). RRo development in MP was largely correlated with the presence of respiratory modulation in the LFP. By showing that the respiratory rhythm influenced brain activities deep to the MP of nonolfactory neurons, our data support the idea that respiratory rhythm could mediate long-range communication between brain areas.NEW & NOTEWORTHY In this study, we evidenced strong respiratory-driven oscillations of neuronal membrane potential and spiking discharge in various nonolfactory areas of the mammal brain. These oscillations were found in the medial prefrontal cortex, primary somatosensory cortex, primary visual cortex, and hippocampus. These findings support the idea that respiratory rhythm could be used as a common clock to set the dynamics of large-scale neuronal networks on the same slow rhythm.

Controlling morpho-electrophysiological variability of neurons with detailed biophysical models.

Variability, which is known to be a universal feature among biological units such as neuronal cells, holds significant importance, as, for example, it enables a robust encoding of a high volume of information in neuronal circuits and prevents hypersynchronizations. While most computational studies on electrophysiological variability in neuronal circuits were done with single-compartment neuron models, we instead focus on the variability of detailed biophysical models of neuron multi-compartmental morphologies. We leverage a Markov chain Monte Carlo method to generate populations of electrical models reproducing the variability of experimental recordings while being compatible with a set of morphologies to faithfully represent specifi morpho-electrical type. We demonstrate our approach on layer 5 pyramidal cells and study the morpho-electrical variability and in particular, find that morphological variability alone is insufficient to reproduce electrical variability. Overall, this approach provides a strong statistical basis to create detailed models of neurons with controlled variability.

Afterhyperpolarization Promotes the Firing of Mitral Cells through a Voltage-Dependent Modification of Action Potential Threshold.

In the olfactory bulb, mitral cells (MCs) display a spontaneous firing that is characterized by bursts of action potentials (APs) intermixed with silent periods. Intraburst firing frequency and duration are heterogeneous among MCs and increase with membrane depolarization. By using patch-clamp recording on rat slices, we dissected out the intrinsic properties responsible for this bursting activity. We showed that the threshold of AP generation dynamically changes as a function of the preceding trajectory of the membrane potential. In fact, the AP threshold became more negative when the membrane was hyperpolarized and had a recovery rate inversely proportional to the membrane repolarization rate. Such variations appeared to be produced by changes in the inactivation state of voltage-dependent Na+ channels. Thus, AP initiation was favored by hyperpolarizing events, such as negative membrane oscillations or inhibitory synaptic input. After the first AP, the following fast afterhyperpolarization (AHP) brought the threshold to more negative values and then promoted the emission of the following AP. This phenomenon was repeated for each AP of the burst making the fast AHP a regenerative mechanism that sustained the firing, AHP with larger amplitudes and faster repolarizations being associated with larger and higher-frequency bursts. Burst termination was found to be because of the development of a slow repolarization component of the AHP (slow AHP). Overall, the AHP characteristics appeared as a major determinant of the bursting properties.

Homeostatic regulation of axonal Kv1.1 channels accounts for both synaptic and intrinsic modifications in the hippocampal CA3 circuit.

Homeostatic plasticity of intrinsic excitability goes hand in hand with homeostatic plasticity of synaptic transmission. However, the mechanisms linking the two forms of homeostatic regulation have not been identified so far. Using electrophysiological, imaging, and immunohistochemical techniques, we show here that blockade of excitatory synaptic receptors for 2 to 3 d induces an up-regulation of both synaptic transmission at CA3-CA3 connections and intrinsic excitability of CA3 pyramidal neurons. Intrinsic plasticity was found to be mediated by a reduction of Kv1.1 channel density at the axon initial segment. In activity-deprived circuits, CA3-CA3 synapses were found to express a high release probability, an insensitivity to dendrotoxin, and a lack of depolarization-induced presynaptic facilitation, indicating a reduction in presynaptic Kv1.1 function. Further support for the down-regulation of axonal Kv1.1 channels in activity-deprived neurons was the broadening of action potentials measured in the axon. We conclude that regulation of the axonal Kv1.1 channel constitutes a major mechanism linking intrinsic excitability and synaptic strength that accounts for the functional synergy existing between homeostatic regulation of intrinsic excitability and synaptic transmission.

A Quick and Easy Way to Estimate Entropy and Mutual Information for Neuroscience.

Calculations of entropy of a signal or mutual information between two variables are valuable analytical tools in the field of neuroscience. They can be applied to all types of data, capture non-linear interactions and are model independent. Yet the limited size and number of recordings one can collect in a series of experiments makes their calculation highly prone to sampling bias. Mathematical methods to overcome this so-called "sampling disaster" exist, but require significant expertise, great time and computational costs. As such, there is a need for a simple, unbiased and computationally efficient tool for estimating the level of entropy and mutual information. In this article, we propose that application of entropy-encoding compression algorithms widely used in text and image compression fulfill these requirements. By simply saving the signal in PNG picture format and measuring the size of the file on the hard drive, we can estimate entropy changes through different conditions. Furthermore, with some simple modifications of the PNG file, we can also estimate the evolution of mutual information between a stimulus and the observed responses through different conditions. We first demonstrate the applicability of this method using white-noise-like signals. Then, while this method can be used in all kind of experimental conditions, we provide examples of its application in patch-clamp recordings, detection of place cells and histological data. Although this method does not give an absolute value of entropy or mutual information, it is mathematically correct, and its simplicity and broad use make it a powerful tool for their estimation through experiments.

Axonal Na+ channels detect and transmit levels of input synchrony in local brain circuits.

Sensory processing requires mechanisms of fast coincidence detection to discriminate synchronous from asynchronous inputs. Spike threshold adaptation enables such a discrimination but is ineffective in transmitting this information to the network. We show here that presynaptic axonal sodium channels read and transmit precise levels of input synchrony to the postsynaptic cell by modulating the presynaptic action potential (AP) amplitude. As a consequence, synaptic transmission is facilitated at cortical synapses when the presynaptic spike is produced by synchronous inputs. Using dual soma-axon recordings, imaging, and modeling, we show that this facilitation results from enhanced AP amplitude in the axon due to minimized inactivation of axonal sodium channels. Quantifying local circuit activity and using network modeling, we found that spikes induced by synchronous inputs produced a larger effect on network activity than spikes induced by asynchronous inputs. Therefore, this input synchrony-dependent facilitation may constitute a powerful mechanism, regulating synaptic transmission at proximal synapses.

Corrigendum: Myelination Increases the Spatial Extent of Analog-Digital Modulation of Synaptic Transmission: A Modeling Study.

[This corrects the article DOI: 10.3389/fncel.2020.00040.].

Myelination Increases the Spatial Extent of Analog-Digital Modulation of Synaptic Transmission: A Modeling Study.

Analog-digital facilitations (ADFs) have been described in local excitatory brain circuits and correspond to a class of phenomena describing how subthreshold variations of the presynaptic membrane potential influence spike-evoked synaptic transmission. In many brain circuits, ADFs rely on the propagation of somatic membrane potential fluctuations to the presynaptic bouton where they modulate ion channels availability, inducing modifications of the presynaptic spike waveform, the spike-evoked Ca2+ entry, and the transmitter release. Therefore, one major requirement for ADFs to occur is the propagation of subthreshold membrane potential variations from the soma to the presynaptic bouton. To date, reported ADFs space constants are relatively short (250-500 µm) which limits their action to proximal synapses. However, ADFs have been studied either in unmyelinated axons or in juvenile animals in which myelination is incomplete. We examined here the potential gain of ADFs spatial extent caused by myelination using a realistic model of L5 pyramidal cell. Myelination of the axon was found to induce a 3-fold increase in the axonal length constant. As a result, the different forms of ADF were found to display a much longer spatial extent (up to 3,000 µm). In addition, while the internodal length displayed a mild effect, the number of myelin wraps ensheathing the internodes was found to play a critical role in the ADFs spatial extents. We conclude that axonal myelination induces an increase in ADFs spatial extent in our model, thus making ADFs plausible in long-distance connections.

Past and Future of Analog-Digital Modulation of Synaptic Transmission.

Action potentials (APs) are generally produced in response to complex summation of excitatory and inhibitory synaptic inputs. While it is usually considered as a digital event, both the amplitude and width of the AP are significantly impacted by the context of its emission. In particular, the analog variations in subthreshold membrane potential determine the spike waveform and subsequently affect synaptic strength, leading to the so-called analog-digital modulation of synaptic transmission. We review here the numerous evidence suggesting context-dependent modulation of spike waveform, the discovery analog-digital modulation of synaptic transmission in invertebrates and its recent validation in mammals. We discuss the potential roles of analog-digital transmission in the physiology of neural networks.

Signal propagation along the axon.

Axons link distant brain regions and are usually considered as simple transmission cables in which reliable propagation occurs once an action potential has been generated. Safe propagation of action potentials relies on specific ion channel expression at strategic points of the axon such as nodes of Ranvier or axonal branch points. However, while action potentials are generally considered as the quantum of neuronal information, their signaling is not entirely digital. In fact, both their shape and their conduction speed have been shown to be modulated by activity, leading to regulations of synaptic latency and synaptic strength. We report here newly identified mechanisms of (1) safe spike propagation along the axon, (2) compartmentalization of action potential shape in the axon, (3) analog modulation of spike-evoked synaptic transmission and (4) alteration in conduction time after persistent regulation of axon morphology in central neurons. We discuss the contribution of these regulations in information processing.

LGI1 tunes intrinsic excitability by regulating the density of axonal Kv1 channels.

Autosomal dominant epilepsy with auditory features results from mutations in leucine-rich glioma-inactivated 1 (LGI1), a soluble glycoprotein secreted by neurons. Animal models of LGI1 depletion display spontaneous seizures, however, the function of LGI1 and the mechanisms by which deficiency leads to epilepsy are unknown. We investigated the effects of pure recombinant LGI1 and genetic depletion on intrinsic excitability, in the absence of synaptic input, in hippocampal CA3 neurons, a classical focus for epileptogenesis. Our data indicate that LGI1 is expressed at the axonal initial segment and regulates action potential firing by setting the density of the axonal Kv1.1 channels that underlie dendrotoxin-sensitive D-type potassium current. LGI1 deficiency incurs a >50% down-regulation of the expression of Kv1.1 and Kv1.2 via a posttranscriptional mechanism, resulting in a reduction in the capacity of axonal D-type current to limit glutamate release, thus contributing to epileptogenesis.

The role of axonal Kv1 channels in CA3 pyramidal cell excitability.

Axonal ion channels control spike initiation and propagation along the axon and determine action potential waveform. We show here that functional suppression of axonal Kv1 channels with local puff of dendrotoxin (DTx), laser or mechanical axotomy significantly increased excitability measured in the cell body. Importantly, the functional effect of DTx puffing or axotomy was not limited to the axon initial segment but was also seen on axon collaterals. In contrast, no effects were observed when DTx was puffed on single apical dendrites or after single dendrotomy. A simple model with Kv1 located in the axon reproduced the experimental observations and showed that the distance at which the effects of axon collateral cuts are seen depends on the axon space constant. In conclusion, Kv1 channels located in the axon proper greatly participate in intrinsic excitability of CA3 pyramidal neurons. This finding stresses the importance of the axonal compartment in the regulation of intrinsic neuronal excitability.

Dynamic Control of Neurotransmitter Release by Presynaptic Potential.

Action potentials (APs) in the mammalian brain are thought to represent the smallest unit of information transmitted by neurons to their postsynaptic targets. According to this view, neuronal signaling is all-or-none or digital. Increasing evidence suggests, however, that subthreshold changes in presynaptic membrane potential before triggering the spike also determines spike-evoked release of neurotransmitter. We discuss here how analog changes in presynaptic voltage may regulate spike-evoked release of neurotransmitter through the modulation of biophysical state of voltage-gated potassium, calcium and sodium channels in the presynaptic compartment. The contribution of this regulation has been greatly underestimated and we discuss the impact for information processing in neuronal circuits.

Presynaptic hyperpolarization induces a fast analogue modulation of spike-evoked transmission mediated by axonal sodium channels.

In the mammalian brain, synaptic transmission usually depends on presynaptic action potentials (APs) in an all-or-none (or digital) manner. Recent studies suggest, however, that subthreshold depolarization in the presynaptic cell facilitates spike-evoked transmission, thus creating an analogue modulation of a digital process (or analogue-digital (AD) modulation). At most synapses, this process is slow and not ideally suited for the fast dynamics of neural networks. We show here that transmission at CA3-CA3 and L5-L5 synapses can be enhanced by brief presynaptic hyperpolarization such as an inhibitory postsynaptic potential (IPSP). Using dual soma-axon patch recordings and live imaging, we find that this hyperpolarization-induced AD facilitation (h-ADF) is due to the recovery from inactivation of Nav channels controlling AP amplitude in the axon. Incorporated in a network model, h-ADF promotes both pyramidal cell synchrony and gamma oscillations. In conclusion, cortical excitatory synapses in local circuits display hyperpolarization-induced facilitation of spike-evoked synaptic transmission that promotes network synchrony.

Analog modulation of spike-evoked transmission in CA3 circuits is determined by axonal Kv1.1 channels in a time-dependent manner.

Synaptic transmission usually depends on action potentials (APs) in an all-or-none (digital) fashion. Recent studies indicate, however, that subthreshold presynaptic depolarization may facilitate spike-evoked transmission, thus creating an analog modulation of spike-evoked synaptic transmission, also called analog-digital (AD) synaptic facilitation. Yet, the underlying mechanisms behind this facilitation remain unclear. We show here that AD facilitation at rat CA3-CA3 synapses is time-dependent and requires long presynaptic depolarization (5-10 s) for its induction. This depolarization-induced AD facilitation (d-ADF) is blocked by the specific Kv1.1 channel blocker dendrotoxin-K. Using fast voltage-imaging of the axon, we show that somatic depolarization used for induction of d-ADF broadened the AP in the axon through inactivation of Kv1.1 channels. Somatic depolarization enhanced spike-evoked calcium signals in presynaptic terminals, but not basal calcium. In conclusion, axonal Kv1.1 channels determine glutamate release in CA3 neurons in a time-dependent manner through the control of the presynaptic spike waveform.

Modulation of spike-evoked synaptic transmission: The role of presynaptic calcium and potassium channels.

Action potentials are usually considered as the smallest unit of neuronal information conveyed by presynaptic neurons to their postsynaptic target. Thus, neuronal signaling in brain circuits is all-or-none or digital. However, recent studies indicate that subthreshold analog variation in presynaptic membrane potential modulates spike-evoked transmission. The informational content of each presynaptic action potential is therefore greater than initially expected. This property constitutes a form of fast activity-dependent modulation of functional coupling. Therefore, it could have important consequences on information processing in neural networks in parallel with more classical forms of presynaptic short-term facilitation based on repetitive stimulation, modulation of presynaptic calcium or modifications of the release machinery. We discuss here how analog voltage shift in the presynaptic neuron may regulate spike-evoked release of neurotransmitter through the modulation of voltage-gated calcium and potassium channels in the axon and presynaptic terminal. This article is part of a Special Issue entitled: 13th European Symposium on Calcium.