Interaction of the mechanosensitive microswimmer Paramecium with obstacles.

In this work, we report investigations of the swimming behaviour of Paramecium tetraurelia, a unicellular microorganism, in micro-engineered pools that are decorated with thousands of cylindrical pillars. Two types of contact interactions are measured, either passive scattering of Paramecium along the obstacle or avoiding reactions (ARs), characterized by an initial backward swimming upon contact, followed by a reorientation before resuming forward motion. We find that ARs are only mechanically triggered approximately 10% of the time. In addition, we observe that only a third of all ARs triggered by contact are instantaneous while two-thirds are delayed by approximately 150 ms. These measurements are consistent with a simple electrophysiological model of mechanotransduction composed of a strong transient current followed by a persistent one upon prolonged contact. This is in apparent contrast with previous electrophysiological measurements where immobilized cells were stimulated with thin probes, which showed instantaneous behavioural responses and no persistent current. Our findings highlight the importance of ecologically relevant approaches to unravel the motility of mechanosensitive microorganisms in complex environments.

An electrophysiological and kinematic model of Paramecium, the "swimming neuron".

Paramecium is a large unicellular organism that swims in fresh water using cilia. When stimulated by various means (mechanically, chemically, optically, thermally), it often swims backward then turns and swims forward again in a new direction: this is called the avoiding reaction. This reaction is triggered by a calcium-based action potential. For this reason, several authors have called Paramecium the "swimming neuron". Here we present an empirically constrained model of its action potential based on electrophysiology experiments on live immobilized paramecia, together with simultaneous measurement of ciliary beating using particle image velocimetry. Using these measurements and additional behavioral measurements of free swimming, we extend the electrophysiological model by coupling calcium concentration to kinematic parameters, turning it into a swimming model. In this way, we obtain a model of autonomously behaving Paramecium. Finally, we demonstrate how the modeled organism interacts with an environment, can follow gradients and display collective behavior. This work provides a modeling basis for investigating the physiological basis of autonomous behavior of Paramecium in ecological environments.

Does the present moment depend on the moments not lived?

Integrated information theory postulates that a conscious experience depends on a repertoire of hypothetical experiences (the axiom of information). This makes consciousness depend on the context that constrains the set of possibilities and on the scenarios imagined by the external observer, and not only on the system itself.

[A critique of the managerial model of research]. / Le modèle managérial de la recherche - Critique et alternative.

To be a scientist is to make an implicit ethical commitment: to try to tell the truth about the world. The managerial model of research, which is the ideological foundation of modern political reforms of the research system around the world, stands in direct conflict with this assertion. It consists in identifying the scientist with a homo economicus looking to maximize its own profit, which a bureaucracy is tasked to align with performance objectives. This model is incoherent and destructive. Science is made possible by curiosity, emulation and intellectual ethics. These are the human traits that a rational research organization should try to favor and exploit.

TITLE: Le modèle managérial de la recherche - Critique et alternative. ABSTRACT: Faire de la science est un engagement moral : s'efforcer de dire le vrai sur le monde. Le modèle managérial de la recherche, fondement idéologique des réformes du système de recherche engagées en France depuis les années 2000, s'y oppose frontalement. Il consiste à identifier le chercheur à un homo economicus cherchant en premier lieu à maximiser son intérêt personnel, qu'une bureaucratie tente d'aligner sur des objectifs de performance chiffrés. Ce modèle est incohérent et destructeur. La science est permise par la curiosité, l'émulation et l'éthique intellectuelle. Ce sont donc ces traits humains qu'une organisation rationnelle de la recherche doit tenter de favoriser et d'exploiter.

Neural excitability increases with axonal resistance between soma and axon initial segment.

The position of the axon initial segment (AIS) is thought to play a critical role in neuronal excitability. Previous experimental studies have found that a distal shift in AIS position correlates with a reduction in excitability. Yet theoretical work has suggested the opposite, because of increased electrical isolation. A distal shift in AIS position corresponds to an elevation of axial resistance Ra We therefore examined how changes in Ra at the axon hillock impact the voltage threshold (Vth) of the somatic action potential in L5 pyramidal neurons. Increasing Ra by mechanically pinching the axon between the soma and the AIS was found to lower Vth by ∼6 mV. Conversely, decreasing Ra by substituting internal ions with higher mobility elevated Vth All Ra -dependent changes in Vth could be reproduced in a Hodgkin-Huxley compartmental model. We conclude that in L5 pyramidal neurons, excitability increases with axial resistance and therefore with a distal shift of the AIS.

Integrative Neuroscience of Paramecium, a "Swimming Neuron".

Paramecium is a unicellular organism that swims in fresh water by beating thousands of cilia. When it is stimulated (mechanically, chemically, optically, thermally…), it often swims backward then turns and swims forward again. This "avoiding reaction" is triggered by a calcium-based action potential. For this reason, some authors have called Paramecium a "swimming neuron." This review summarizes current knowledge about the physiological basis of behavior of Paramecium.

Electrical match between initial segment and somatodendritic compartment for action potential backpropagation in retinal ganglion cells.

The action potential of most vertebrate neurons initiates in the axon initial segment (AIS) and is then transmitted to the soma where it is regenerated by somatodendritic sodium channels. For successful transmission, the AIS must produce a strong axial current, so as to depolarize the soma to the threshold for somatic regeneration. Theoretically, this axial current depends on AIS geometry and Na+ conductance density. We measured the axial current of mouse retinal ganglion cells using whole cell recordings with post hoc AIS labeling. We found that this current is large, implying high Na+ conductance density, and carries a charge that covaries with capacitance so as to depolarize the soma by ∼30 mV. Additionally, we observed that the axial current attenuates strongly with depolarization, consistent with sodium channel inactivation, but temporally broadens so as to preserve the transmitted charge. Thus, the AIS appears to be organized so as to reliably backpropagate the axonal action potential.NEW & NOTEWORTHY We measured the axial current produced at spike initiation by the axon initial segment of mouse retinal ganglion cells. We found that it is a large current, requiring high sodium channel conductance density, which covaries with cell capacitance so as to ensure a ∼30 mV depolarization. During sustained depolarization the current attenuated, but it broadened to preserve somatic depolarization. Thus, properties of the initial segment are adjusted to ensure backpropagation of the axonal action potential.

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.

A simple device to immobilize protists for electrophysiology and microinjection.

We present a simple device to mechanically immobilize motile cells such as ciliates. It can be used in particular for intracellular electrophysiology and microinjection. A transparent filter with holes smaller than the specimen is stretched over an outlet. A flow is induced by either a peristaltic pump or a depressurized tank, mechanically entraining cells to the bottom, where they are immobilized against the filter. The cells start swimming again as soon as the flow is stopped. We demonstrate the device by recording action potentials in Paramecium and injecting a fluorescent dye into the cytosol.

Theoretical relation between axon initial segment geometry and excitability.

In most vertebrate neurons, action potentials are triggered at the distal end of the axon initial segment (AIS). Both position and length of the AIS vary across and within neuron types, with activity, development and pathology. What is the impact of AIS geometry on excitability? Direct empirical assessment has proven difficult because of the many potential confounding factors. Here, we carried a principled theoretical analysis to answer this question. We provide a simple formula relating AIS geometry and sodium conductance density to the somatic voltage threshold. A distal shift of the AIS normally produces a (modest) increase in excitability, but we explain how this pattern can reverse if a hyperpolarizing current is present at the AIS, due to resistive coupling with the soma. This work provides a theoretical tool to assess the significance of structural AIS plasticity for electrical function.

Neural coding: The bureaucratic model of the brain.

The neural coding metaphor is so ubiquitous that we tend to forget its metaphorical nature. What do we mean when we assert that neurons encode and decode? What kind of causal and representational model of the brain does the metaphor entail? What lies beneath the neural coding metaphor, I argue, is a bureaucratic model of the brain.

Anticipatory coadaptation of ankle stiffness and sensorimotor gain for standing balance.

External perturbation forces may compromise standing balance. The nervous system can intervene only after a delay greater than 100 ms, during which the body falls freely. With ageing, sensorimotor delays are prolonged, posing a critical threat to balance. We study a generic model of stabilisation with neural delays to understand how the organism should adapt to challenging balance conditions. The model suggests that ankle stiffness should be increased in anticipation of perturbations, for example by muscle co-contraction, so as to slow down body fall during the neural response delay. Increased ankle muscle co-contraction is indeed observed in young adults when standing in challenging balance conditions, and in older relative to young adults during normal stance. In parallel, the analysis of the model shows that increases in either stiffness or neural delay must be coordinated with decreases in spinal sensorimotor gains, otherwise the feedback itself becomes destabilizing. Accordingly, a decrease in spinal feedback is observed in challenging conditions, and with age-related increases in neural delay. These observations have been previously interpreted as indicating an increased reliance on cortical rather than spinal control of balance, despite the fact that cortical responses have a longer latency. Our analysis challenges this interpretation by showing that these observations are consistent with a functional coadaptation of spinal feedback gains to functional changes in stiffness and neural delay.

Brian 2, an intuitive and efficient neural simulator.

Brian 2 allows scientists to simply and efficiently simulate spiking neural network models. These models can feature novel dynamical equations, their interactions with the environment, and experimental protocols. To preserve high performance when defining new models, most simulators offer two options: low-level programming or description languages. The first option requires expertise, is prone to errors, and is problematic for reproducibility. The second option cannot describe all aspects of a computational experiment, such as the potentially complex logic of a stimulation protocol. Brian addresses these issues using runtime code generation. Scientists write code with simple and concise high-level descriptions, and Brian transforms them into efficient low-level code that can run interleaved with their code. We illustrate this with several challenging examples: a plastic model of the pyloric network, a closed-loop sensorimotor model, a programmatic exploration of a neuron model, and an auditory model with real-time input.

Postural adjustments in anticipation of predictable perturbations allow elderly fallers to achieve a balance recovery performance equivalent to elderly non-fallers.

BACKGROUND: In numerous laboratory-based perturbation experiments, differences in the balance recovery performance of elderly fallers and non-fallers are moderate or absent. This performance may be affected by the subjects adjusting their initial posture in anticipation of the perturbation. RESEARCH QUESTIONS: Do elderly fallers and non-fallers adjust their posture in anticipation of externally-imposed perturbations in a laboratory setting? How does this impact their balance recovery performance? METHODS: 21 elderly non-fallers, 18 age-matched elderly fallers and 11 young adults performed both a forward waist-pull perturbation task and a Choice Stepping Reaction Time (CSRT) task. Whole-body kinematics and ground reaction forces were recorded. For each group, we evaluated the balance recovery performance in the perturbation task, change in initial center of mass (CoM) position between the CSRT and the perturbation task, and the influence of initial CoM position on task performance. RESULTS: The balance recovery performance of elderly fallers was equivalent to elderly non-fallers (p > 0.5 Kolmogorov-Smirnov test). All subject groups anticipated forward perturbations by shifting their CoM backward compared to the CSRT task (young: 2.1% of lower limb length, elderly non-fallers: 2.7%, elderly fallers: 2.2%, Hodges-Lehmann estimator, p < 0.001 Mann-Whitney U). This backward shift increases the probability of resisting the traction without taking a step. SIGNIFICANCE: The ability to anticipate perturbations is preserved in elderly fallers and may explain their preserved balance recovery performance in laboratory-based perturbation tasks. Therefore, future fall risk prediction studies should carefully control for this postural strategy, by interleaving perturbations of different directions for example.

Code Generation in Computational Neuroscience: A Review of Tools and Techniques.

Advances in experimental techniques and computational power allowing researchers to gather anatomical and electrophysiological data at unprecedented levels of detail have fostered the development of increasingly complex models in computational neuroscience. Large-scale, biophysically detailed cell models pose a particular set of computational challenges, and this has led to the development of a number of domain-specific simulators. At the other level of detail, the ever growing variety of point neuron models increases the implementation barrier even for those based on the relatively simple integrate-and-fire neuron model. Independently of the model complexity, all modeling methods crucially depend on an efficient and accurate transformation of mathematical model descriptions into efficiently executable code. Neuroscientists usually publish model descriptions in terms of the mathematical equations underlying them. However, actually simulating them requires they be translated into code. This can cause problems because errors may be introduced if this process is carried out by hand, and code written by neuroscientists may not be very computationally efficient. Furthermore, the translated code might be generated for different hardware platforms, operating system variants or even written in different languages and thus cannot easily be combined or even compared. Two main approaches to addressing this issues have been followed. The first is to limit users to a fixed set of optimized models, which limits flexibility. The second is to allow model definitions in a high level interpreted language, although this may limit performance. Recently, a third approach has become increasingly popular: using code generation to automatically translate high level descriptions into efficient low level code to combine the best of previous approaches. This approach also greatly enriches efforts to standardize simulator-independent model description languages. In the past few years, a number of code generation pipelines have been developed in the computational neuroscience community, which differ considerably in aim, scope and functionality. This article provides an overview of existing pipelines currently used within the community and contrasts their capabilities and the technologies and concepts behind them.

Contribution of the Axon Initial Segment to Action Potentials Recorded Extracellularly.

Action potentials (APs) are electric phenomena that are recorded both intracellularly and extracellularly. APs are usually initiated in the short segment of the axon called the axon initial segment (AIS). It was recently proposed that at the onset of an AP the soma and the AIS form a dipole. We study the extracellular signature [the extracellular AP (EAP)] generated by such a dipole. First, we demonstrate the formation of the dipole and its extracellular signature in detailed morphological models of a reconstructed pyramidal neuron. Then, we study the EAP waveform and its spatial dependence in models with axonal AP initiation and contrast it with the EAP obtained in models with somatic AP initiation. We show that in the models with axonal AP initiation the dipole forms between somatodendritic compartments and the AIS, and not between soma and dendrites as in the classical models. The soma-dendrites dipole is present only in models with somatic AP initiation. Our study has consequences for interpreting extracellular recordings of single-neuron activity and determining electrophysiological neuron types, but also for better understanding the origins of the high-frequency macroscopic extracellular potentials recorded in the brain.

The electrical significance of axon location diversity.

The axon initial segment (AIS) is a unique domain of the proximal axon serving critical electrical and structural roles including the initiation of action potentials and maintenance of cellular polarity. Recent experimental and theoretical advances demonstrate that the anatomical site for initiation is remarkably diverse. The AIS location varies not only axially, along the axon, but axons also emerge variably from either the soma or proximal dendrites. Here, we review the evidence that the diversity of AIS and axon location has a substantial impact on the electrical properties and speculate that the anatomical heterogeneity of axon locations expands synaptic integration within cell types and improves information processing in neural circuits.

Is coding a relevant metaphor for the brain?

"Neural coding" is a popular metaphor in neuroscience, where objective properties of the world are communicated to the brain in the form of spikes. Here I argue that this metaphor is often inappropriate and misleading. First, when neurons are said to encode experimental parameters, the neural code depends on experimental details that are not carried by the coding variable (e.g., the spike count). Thus, the representational power of neural codes is much more limited than generally implied. Second, neural codes carry information only by reference to things with known meaning. In contrast, perceptual systems must build information from relations between sensory signals and actions, forming an internal model. Neural codes are inadequate for this purpose because they are unstructured and therefore unable to represent relations. Third, coding variables are observables tied to the temporality of experiments, whereas spikes are timed actions that mediate coupling in a distributed dynamical system. The coding metaphor tries to fit the dynamic, circular, and distributed causal structure of the brain into a linear chain of transformations between observables, but the two causal structures are incongruent. I conclude that the neural coding metaphor cannot provide a valid basis for theories of brain function, because it is incompatible with both the causal structure of the brain and the representational requirements of cognition.

The world is complex, not just noisy.

To deny that human perception is optimal is not to claim that it is suboptimal. Rahnev & Denison (R&D) point out that optimality is often ill defined. The fundamental issue is framing perception as a statistical inference problem. Outside of the lab, the real perceptual challenge is to determine the lawful structure of the world, not variables of a predetermined statistical model.

Mobility as the Purpose of Postural Control.

Counteracting the destabilizing force of gravity is usually considered to be the main purpose of postural control. However, from the consideration of the mechanical requirements for movement, we argue that posture is adjusted in view of providing impetus for movement. Thus, we show that the posture that is usually adopted in quiet standing in fact allows torque for potential movement. Moreover, when performing a movement-either voluntarily or in response to an external perturbation-we show that the postural adjustments are organized both spatially and temporally so as to provide the required torque for the movement. Thus, when movement is performed skillfully, the force of gravity is not counteracted but actually used to provide impetus to movement. This ability to move one's weight so as to exploit the torque of gravity seems to be dependent on development and skill learning, and is impaired in aging.