Dynamical noise can enhance high-order statistical structure in complex systems

Recent research has provided a wealth of evidence highlighting the pivotal role of high-order interdependencies in supporting the information-processing capabilities of distributed complex systems. These findings may suggest that high-order interdependencies constitute a powerful resource that is, however, challenging to harness and can be readily disrupted. In this paper we contest this perspective by demonstrating that high-order interdependencies can not only exhibit robustness to stochastic perturbations, but can in fact be enhanced by them. Using elementary cellular automata as a general testbed, our results unveil the capacity of dynamical noise to enhance the statistical regularities between agents and, intriguingly, even alter the prevailing character of their interdependencies. Furthermore, our results show that these effects are related to the high-order structure of the local rules, which affect the system's susceptibility to noise and characteristic times-scales. These results deepen our understanding of how high-order interdependencies may spontaneously emerge within distributed systems interacting with stochastic environments, thus providing an initial step towards elucidating their origin and function in complex systems like the human brain.Comment: 8 pages, 4 figures, 2 table

Structural Determinants for Functional Coupling Between the β and α Subunits in the Ca2+-activated K+ (BK) Channel

High conductance, calcium- and voltage-activated potassium (BK, MaxiK) channels are widely expressed in mammals. In some tissues, the biophysical properties of BK channels are highly affected by coexpression of regulatory (β) subunits. The most remarkable effects of β1 and β2 subunits are an increase of the calcium sensitivity and the slow down of channel kinetics. However, the detailed characteristics of channels formed by α and β1 or β2 are dissimilar, the most remarkable difference being a reduction of the voltage sensitivity in the presence of β1 but not β2. Here we reveal the molecular regions in these β subunits that determine their differential functional coupling with the pore-forming α-subunit. We made chimeric constructs between β1 and β2 subunits, and BK channels formed by α and chimeric β subunits were expressed in Xenopus laevis oocytes. The electrophysiological characteristics of the resulting channels were determined using the patch clamp technique. Chimeric exchange of the different regions of the β1 and β2 subunits demonstrates that the NH3 and COOH termini are the most relevant regions in defining the behavior of either subunit. This strongly suggests that the intracellular domains are crucial for the fine tuning of the effects of these β subunits. Moreover, the intracellular domains of β1 are responsible for the reduction of the BK channel voltage dependence. This agrees with previous studies that suggested the intracellular regions of the α-subunit to be the target of the modulation by the β1-subunit

Local topology of connectome stabilizes critical points in mean field model

The interplay between structural connectivity (SC) and neural dynamics is still not yet fully understood. Applying topological analysis, the connectome approach links this anatomical network to brain function. Here we adopt a computational approach to find topology features related to the stability on global neural dynamics. A previous study of a mean field model based on the human cortex network, shows at least 2 global neural states, with either a low or high firing rate pattern. These 2 possible states, or bistability, emerge in the model within a range of the global coupling parameter G, limited by critical values G- and G +.Instituto de Investigaciones en Electrónica, Control y Procesamiento de Señale

Slow Inactivation in Shaker K Channels Is Delayed by Intracellular Tetraethylammonium

After removal of the fast N-type inactivation gate, voltage-sensitive Shaker (Shaker IR) K channels are still able to inactivate, albeit slowly, upon sustained depolarization. The classical mechanism proposed for the slow inactivation observed in cell-free membrane patches—the so called C inactivation—is a constriction of the external mouth of the channel pore that prevents K+ ion conduction. This constriction is antagonized by the external application of the pore blocker tetraethylammonium (TEA). In contrast to C inactivation, here we show that, when recorded in whole Xenopus oocytes, slow inactivation kinetics in Shaker IR K channels is poorly dependent on external TEA but severely delayed by internal TEA. Based on the antagonism with internally or externally added TEA, we used a two-pulse protocol to show that half of the channels inactivate by way of a gate sensitive to internal TEA. Such gate had a recovery time course in the tens of milliseconds range when the interpulse voltage was −90 mV, whereas C-inactivated channels took several seconds to recover. Internal TEA also reduced gating charge conversion associated to slow inactivation, suggesting that the closing of the internal TEA-sensitive inactivation gate could be associated with a significant amount of charge exchange of this type. We interpreted our data assuming that binding of internal TEA antagonized with U-type inactivation (Klemic, K.G., G.E. Kirsch, and S.W. Jones. 2001. Biophys. J. 81:814–826). Our results are consistent with a direct steric interference of internal TEA with an internally located slow inactivation gate as a “foot in the door” mechanism, implying a significant functional overlap between the gate of the internal TEA-sensitive slow inactivation and the primary activation gate. But, because U-type inactivation is reduced by channel opening, trapping the channel in the open conformation by TEA would also yield to an allosteric delay of slow inactivation. These results provide a framework to explain why constitutively C-inactivated channels exhibit gating charge conversion, and why mutations at the internal exit of the pore, such as those associated to episodic ataxia type I in hKv1.1, cause severe changes in inactivation kinetics

Constitutive phosphorylation of serine 29 as a critical regulator of TRPM8 channel function

Resumen del trabajo presentado al VIII Congreso Red Española de Canales Iónicos, celebrado en Alicante del 24 al 27 de mayo de 2022.The main molecular entity involved in innocuous cold detection in mammals is TRPM8. This polymodal TRP channel is activated by cold, cooling compounds such as menthol, voltage, and rises in osmolality. Basal kinase activity phosphorylates TRPM8 and modulates its function under resting conditions. However, which specific residues, how this post-translational modification modulates TRPM8 activity, and its influence on cold sensing are still poorly understood. We identified four serine residues within the N-terminal domain constitutively phosphorylated in the mouse ortholog by mass spectrometry. TRPM8 function was assessed by Ca2+-imaging and patch-clamp recordings, revealing that treatment with staurosporine, a kinase inhibitor, increased cold- and mentholevoked responses of the channel. S29A mutation is sufficient to enhance TRPM8 activity, suggesting that phosphorylation of this residue is a critical molecular determinant of this negative regulation. Biophysical and TIRF-based analysis revealed a dual mechanism in the potentiated responses of unphosphorylated TRPM8: an increase in the number of active channels at the plasma membrane and a shift in the voltage activation curve towards more negative potentials. Notably, basal kinase activity downregulates TRPM8 function at cold thermoreceptor neurons, an observation accounted for by mathematical modeling. Overall, our findings suggest that cold temperature detection could be rapidly and reversibly fine-tuned by controlling the TRPM8 basal phosphorylation state, a mechanism that acts as a dynamic molecular brake of this thermo-TRP channel function in primary sensory neurons.Supported by Grants Millennium Nucleus for the Study of Pain (MiNuSPain) (RM, MP), Millennium Nucleus of Ion Channel-Associated Diseases (MiNICAD) (RM, MP), DICYT VRIDeI-USACH 022143PP (MP, RM) and by VRIDeI-USACH 021843MM (RM).Peer reviewe

Simple, Fast and Accurate Implementation of the Diffusion Approximation Algorithm for Stochastic Ion Channels with Multiple States

The phenomena that emerge from the interaction of the stochastic opening and closing of ion channels (channel noise) with the non-linear neural dynamics are essential to our understanding of the operation of the nervous system. The effects that channel noise can have on neural dynamics are generally studied using numerical simulations of stochastic models. Algorithms based on discrete Markov Chains (MC) seem to be the most reliable and trustworthy, but even optimized algorithms come with a non-negligible computational cost. Diffusion Approximation (DA) methods use Stochastic Differential Equations (SDE) to approximate the behavior of a number of MCs, considerably speeding up simulation times. However, model comparisons have suggested that DA methods did not lead to the same results as in MC modeling in terms of channel noise statistics and effects on excitability. Recently, it was shown that the difference arose because MCs were modeled with coupled activation subunits, while the DA was modeled using uncoupled activation subunits. Implementations of DA with coupled subunits, in the context of a specific kinetic scheme, yielded similar results to MC. However, it remained unclear how to generalize these implementations to different kinetic schemes, or whether they were faster than MC algorithms. Additionally, a steady state approximation was used for the stochastic terms, which, as we show here, can introduce significant inaccuracies. We derived the SDE explicitly for any given ion channel kinetic scheme. The resulting generic equations were surprisingly simple and interpretable - allowing an easy and efficient DA implementation. The algorithm was tested in a voltage clamp simulation and in two different current clamp simulations, yielding the same results as MC modeling. Also, the simulation efficiency of this DA method demonstrated considerable superiority over MC methods.Comment: 32 text pages, 10 figures, 1 supplementary text + figur

Viscous dynamics associated with hypoexcitation and structural disintegration in neurodegeneration via generative whole-brain modeling

INTRODUCTION Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD) lack mechanistic biophysical modeling in diverse, underrepresented populations. Electroencephalography (EEG) is a high temporal resolution, cost-effective technique for studying dementia globally, but lacks mechanistic models and produces non-replicable results. METHODS We developed a generative whole-brain model that combines EEG source-level metaconnectivity, anatomical priors, and a perturbational approach. This model was applied to Global South participants (AD, bvFTD, and healthy controls). RESULTS Metaconnectivity outperformed pairwise connectivity and revealed more viscous dynamics in patients, with altered metaconnectivity patterns associated with multimodal disease presentation. The biophysical model showed that connectome disintegration and hypoexcitability triggered altered metaconnectivity dynamics and identified critical regions for brain stimulation. We replicated the main results in a second subset of participants for validation with unharmonized, heterogeneous recording settings. DISCUSSION The results provide a novel agenda for developing mechanistic model-inspired characterization and therapies in clinical, translational, and computational neuroscience settings

26th Annual Computational Neuroscience Meeting (CNS*2017): Part 3 - Meeting Abstracts - Antwerp, Belgium. 15–20 July 2017

This work was produced as part of the activities of FAPESP Research,\ud Disseminations and Innovation Center for Neuromathematics (grant\ud 2013/07699-0, S. Paulo Research Foundation). NLK is supported by a\ud FAPESP postdoctoral fellowship (grant 2016/03855-5). ACR is partially\ud supported by a CNPq fellowship (grant 306251/2014-0)