A Dendritic Mechanism for Decoding Traveling Waves: Principles and Applications to Motor Cortex

Traveling waves of neuronal oscillations have been observed in many cortical regions, including the motor and sensory cortex. Such waves are often modulated in a task-dependent fashion although their precise functional role remains a matter of debate. Here we conjecture that the cortex can utilize the direction and wavelength of traveling waves to encode information. We present a novel neural mechanism by which such information may be decoded by the spatial arrangement of receptors within the dendritic receptor field. In particular, we show how the density distributions of excitatory and inhibitory receptors can combine to act as a spatial filter of wave patterns. The proposed dendritic mechanism ensures that the neuron selectively responds to specific wave patterns, thus constituting a neural basis of pattern decoding. We validate this proposal in the descending motor system, where we model the large receptor fields of the pyramidal tract neurons — the principle outputs of the motor cortex — decoding motor commands encoded in the direction of traveling wave patterns in motor cortex. We use an existing model of field oscillations in motor cortex to investigate how the topology of the pyramidal cell receptor field acts to tune the cells responses to specific oscillatory wave patterns, even when those patterns are highly degraded. The model replicates key findings of the descending motor system during simple motor tasks, including variable interspike intervals and weak corticospinal coherence. By additionally showing how the nature of the wave patterns can be controlled by modulating the topology of local intra-cortical connections, we hence propose a novel integrated neuronal model of encoding and decoding motor commands.     

A versatile cortical pattern-forming circuit based on Rho,F-actin,Ect2, and RGA-3/4

Many cells can generate complementary traveling waves of actin filaments (F-actin) and cytoskeletal regulators. This phenomenon, termed cortical excitability, results from coupled positive and negative feedback loops of cytoskeletal regulators. The nature of these feedback loops, however, remains poorly understood. We assessed the role of the Rho GAP RGA-3/4 in the cortical excitability that accompanies cytokinesis in both frog and starfish. RGA-3/4 localizes to the cytokinetic apparatus, “chases” Rho waves in an F-actin–dependent manner, and when coexpressed with the Rho GEF Ect2, is sufficient to convert the normally quiescent, immature Xenopus oocyte cortex into a dramatically excited state. Experiments and modeling show that changing the ratio of RGA-3/4 to Ect2 produces cortical behaviors ranging from pulses to complex waves of Rho activity. We conclude that RGA-3/4, Ect2, Rho, and F-actin form the core of a versatile circuit that drives a diverse range of cortical behaviors, and we demonstrate that the immature oocyte is a powerful model for characterizing these dynamics.     

Selection of Multiarmed Spiral Waves in a Regular Network of Neurons

Formation and selection of multiarmed spiral wave due to spontaneous symmetry breaking are investigated in a regular network of Hodgkin-Huxley neuron by changing the excitability and imposing spatial forcing currents on the neurons in the network. The arm number of the multiarmed spiral wave is dependent on the distribution of spatial forcing currents and excitability diversity in the network, and the selection criterion for supporting multiarmed spiral waves is discussed. A broken spiral segment is measured by a short polygonal line connected by three adjacent points (controlled nodes), and a double-spiral wave can be developed from the spiral segment. Multiarmed spiral wave is formed when a group of double-spiral waves rotate in the same direction in the network. In the numerical studies, a group of controlled nodes are selected and spatial forcing currents are imposed on these nodes, and our results show that l-arm stable spiral wave (l = 2, 3, 4,...8) can be induced to occupy the network completely. It is also confirmed that low excitability is critical to induce multiarmed spiral waves while high excitability is important to propagate the multiarmed spiral wave outside so that distinct multiarmed spiral wave can occupy the network completely. Our results confirm that symmetry breaking of target wave in the media accounts for emergence of multiarmed spiral wave, which can be developed from a group of spiral waves with single arm under appropriate condition, thus the potential formation mechanism of multiarmed spiral wave in the media is explained.     

Constitutively active protein kinase A disrupts motility and chemotaxis in Dictyostelium discoideum

The deletion of the gene for the regulatory subunit of protein kinase A (PKA) results in constitutively active PKA in the pkaR mutant. To investigate the role of PKA in the basic motile behavior and chemotaxis of Dictyostelium discoideum, pkaR mutant cells were subjected to computer-assisted two- and three-dimensional motion analysis. pkaR mutant cells crawled at only half the speed of wild-type cells in buffer, chemotaxed in spatial gradients of cyclic AMP (cAMP) but with reduced efficiency, were incapable of suppressing lateral pseudopods in the front of temporal waves of cAMP, a requirement for natural chemotaxis, did not exhibit the normal velocity surge in response to the front of a wave, and were incapable of chemotaxing toward an aggregation center in natural waves generated by wild-type cells that made up the majority of cells in mixed cultures. Many of the behavioral defects appeared to be the result of the constitutively ovoid shape of the pkaR mutant cells, which forced the dominant pseudopod off the substratum and to the top of the cell body. The behavioral abnormalities that pkaR mutant cells shared with regA mutant cells are discussed by considering the pathway ERK2 —| RegA —| [cAMP] → PKA, which emanates from the front of a wave. The results demonstrate that cells must suppress PKA activity in order to elongate along a substratum, suppress lateral-pseudopod formation, and crawl and chemotax efficiently. The results also implicate PKA activation in dismantling cell polarity at the peak and in the back of a natural cAMP wave.     

A Cytotoxic,Co-operative Interaction Between Energy Deprivation and Glutamate Release From System xc? Mediates Aglycemic Neuronal Cell Death

The astrocyte cystine/glutamate antiporter (system x_c⁻) contributes substantially to the excitotoxic neuronal cell death facilitated by glucose deprivation. The purpose of this study was to determine the mechanism by which this occurred. Using pure astrocyte cultures, as well as, mixed cortical cell cultures containing both neurons and astrocytes, we found that neither an enhancement in system x_c⁻ expression nor activity underlies the excitotoxic effects of aglycemia. In addition, using three separate bioassays, we demonstrate no change in the ability of glucose-deprived astrocytes—either cultured alone or with neurons—to remove glutamate from the extracellular space. Instead, we demonstrate that glucose-deprived cultures are 2 to 3 times more sensitive to the killing effects of glutamate or N-methyl-D-aspartate when compared with their glucose-containing controls. Hence, our results are consistent with the weak excitotoxic hypothesis such that a bioenergetic deficiency, which is measureable in our mixed but not astrocyte cultures, allows normally innocuous concentrations of glutamate to become excitotoxic. Adding to the burgeoning literature detailing the contribution of astrocytes to neuronal injury, we conclude that under our experimental paradigm, a cytotoxic, co-operative interaction between energy deprivation and glutamate release from astrocyte system x_c⁻ mediates aglycemic neuronal cell death.     

Food or just a free ride? A meta-analysis reveals the global diversity of the Plastisphere

It is now indisputable that plastics are ubiquitous and problematic in ecosystems globally. Many suggestions have been made about the role that biofilms colonizing plastics in the environment—termed the “Plastisphere”—may play in the transportation and ecological impact of these plastics. By collecting and re-analyzing all raw 16S rRNA gene sequencing and metadata from 2,229 samples within 35 studies, we have performed the first meta-analysis of the Plastisphere in marine, freshwater, other aquatic (e.g., brackish or aquaculture) and terrestrial environments. We show that random forest models can be trained to differentiate between groupings of environmental factors as well as aspects of study design, but—crucially—also between plastics when compared with control biofilms and between different plastic types and community successional stages. Our meta-analysis confirms that potentially biodegrading Plastisphere members, the hydrocarbonoclastic Oceanospirillales and Alteromonadales are consistently more abundant in plastic than control biofilm samples across multiple studies and environments. This indicates the predilection of these organisms for plastics and confirms the urgent need for their ability to biodegrade plastics to be comprehensively tested. We also identified key knowledge gaps that should be addressed by future studies.Subject terms: Microbial ecology, Soil microbiology, Water microbiology, Microbial ecology, Microbiome     

Spatial trigger waves: positive feedback gets you a long way

Trigger waves are a recurring biological phenomenon involved in transmitting information quickly and reliably over large distances. Well-characterized examples include action potentials propagating along the axon of a neuron, calcium waves in various tissues, and mitotic waves in Xenopus eggs. Here we use the FitzHugh-Nagumo model, a simple model inspired by the action potential that is widely used in physics and theoretical biology, to examine different types of trigger waves—spatial switches, pulses, and oscillations—and to show how they arise.     

Identification of an Interaction between VWF rs7965413 and Platelet Count as a Novel Risk Marker for Metabolic Syndrome: An Extensive Search of Candidate Polymorphisms in a Case-Control Study

Although many single nucleotide polymorphisms (SNPs) have been identified to be associated with metabolic syndrome (MetS), there was only a slight improvement in the ability to predict future MetS by the simply addition of SNPs to clinical risk markers. To improve the ability to predict future MetS, combinational effects, such as SNP—SNP interaction, SNP—environment interaction, and SNP—clinical parameter (SNP × CP) interaction should be also considered. We performed a case-control study to explore novel SNP × CP interactions as risk markers for MetS based on health check-up data of Japanese male employees. We selected 99 SNPs that were previously reported to be associated with MetS and components of MetS; subsequently, we genotyped these SNPs from 360 cases and 1983 control subjects. First, we performed logistic regression analyses to assess the association of each SNP with MetS. Of these SNPs, five SNPs were significantly associated with MetS (P < 0.05): LRP2 rs2544390, rs1800592 between UCP1 and TBC1D9, APOA5 rs662799, VWF rs7965413, and rs1411766 between MYO16 and IRS2. Furthermore, we performed multiple logistic regression analyses, including an SNP term, a CP term, and an SNP × CP interaction term for each CP and SNP that was significantly associated with MetS. We identified a novel SNP × CP interaction between rs7965413 and platelet count that was significantly associated with MetS [SNP term: odds ratio (OR) = 0.78, P = 0.004; SNP × CP interaction term: OR = 1.33, P = 0.001]. This association of the SNP × CP interaction with MetS remained nominally significant in multiple logistic regression analysis after adjustment for either the number of MetS components or MetS components excluding obesity. Our results reveal new insight into platelet count as a risk marker for MetS.     

Cell cycle–regulated membrane binding of NuMA contributes to efficient anaphase chromosome separation

Accurate and efficient separation of sister chromatids during anaphase is critical for faithful cell division. It has been proposed that cortical dynein–generated pulling forces on astral microtubules contribute to anaphase spindle elongation and chromosome separation. In mammalian cells, however, definitive evidence for the involvement of cortical dynein in chromosome separation is missing. It is believed that dynein is recruited and anchored at the cell cortex during mitosis by the α subunit of heterotrimeric G protein (Gα)/mammalian homologue of Drosophila Partner of Inscuteable/nuclear mitotic apparatus (NuMA) ternary complex. Here we uncover a Gα/LGN-independent lipid- and membrane-binding domain at the C-terminus of NuMA. We show that the membrane binding of NuMA is cell cycle regulated—it is inhibited during prophase and metaphase by cyclin-dependent kinase 1 (CDK1)–mediated phosphorylation and only occurs after anaphase onset when CDK1 activity is down-regulated. Further studies indicate that cell cycle–regulated membrane association of NuMA underlies anaphase-specific enhancement of cortical NuMA and dynein. By replacing endogenous NuMA with membrane-binding-deficient NuMA, we can specifically reduce the cortical accumulation of NuMA and dynein during anaphase and demonstrate that cortical NuMA and dynein contribute to efficient chromosome separation in mammalian cells.     

Modeling a disease-correlated tubulin mutation in budding yeast reveals insight into MAP-mediated dynein function

Mutations in the genes that encode α- and β-tubulin underlie many neurological diseases, most notably malformations in cortical development. In addition to revealing the molecular basis for disease etiology, studying such mutations can provide insight into microtubule function and the role of the large family of microtubule effectors. In this study, we use budding yeast to model one such mutation—Gly436Arg in α-tubulin, which is causative of malformations in cortical development—in order to understand how it impacts microtubule function in a simple eukaryotic system. Using a combination of in vitro and in vivo methodologies, including live cell imaging and electron tomography, we find that the mutant tubulin is incorporated into microtubules, causes a shift in α-tubulin isotype usage, and dramatically enhances dynein activity, which leads to spindle-positioning defects. We find that the basis for the latter phenotype is an impaired interaction between She1—a dynein inhibitor—and the mutant microtubules. In addition to revealing the natural balance of α-tubulin isotype utilization in cells, our results provide evidence of an impaired interaction between microtubules and a dynein regulator as a consequence of a tubulin mutation and sheds light on a mechanism that may be causative of neurodevelopmental diseases.     

Anthranilate Fluorescence Marks a Calcium-Propagated Necrotic Wave That Promotes Organismal Death in C. elegans

For cells the passage from life to death can involve a regulated, programmed transition. In contrast to cell death, the mechanisms of systemic collapse underlying organismal death remain poorly understood. Here we present evidence of a cascade of cell death involving the calpain-cathepsin necrosis pathway that can drive organismal death in Caenorhabditis elegans. We report that organismal death is accompanied by a burst of intense blue fluorescence, generated within intestinal cells by the necrotic cell death pathway. Such death fluorescence marks an anterior to posterior wave of intestinal cell death that is accompanied by cytosolic acidosis. This wave is propagated via the innexin INX-16, likely by calcium influx. Notably, inhibition of systemic necrosis can delay stress-induced death. We also identify the source of the blue fluorescence, initially present in intestinal lysosome-related organelles (gut granules), as anthranilic acid glucosyl esters—not, as previously surmised, the damage product lipofuscin. Anthranilic acid is derived from tryptophan by action of the kynurenine pathway. These findings reveal a central mechanism of organismal death in C. elegans that is related to necrotic propagation in mammals—e.g., in excitotoxicity and ischemia-induced neurodegeneration. Endogenous anthranilate fluorescence renders visible the spatio-temporal dynamics of C. elegans organismal death.     

Real-Time Changes in Corticospinal Excitability during Voluntary Contraction with Concurrent Electrical Stimulation

While previous studies have assessed changes in corticospinal excitability following voluntary contraction coupled with electrical stimulation (ES), we sought to examine, for the first time in the field, real-time changes in corticospinal excitability. We monitored motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation and recorded the MEPs using a mechanomyogram, which is less susceptible to electrical artifacts. We assessed the MEPs at each level of muscle contraction of wrist flexion (0%, 5%, or 20% of maximum voluntary contraction) during voluntary wrist flexion (flexor carpi radialis (FCR) voluntary contraction), either with or without simultaneous low-frequency (10 Hz) ES of the median nerve that innervates the FCR. The stimulus intensity corresponded to 1.2× perception threshold. In the FCR, voluntary contraction with median nerve stimulation significantly increased corticospinal excitability compared with FCR voluntary contraction without median nerve stimulation (p<0.01). In addition, corticospinal excitability was significantly modulated by the level of FCR voluntary contraction. In contrast, in the extensor carpi radialis (ECR), FCR voluntary contraction with median nerve stimulation significantly decreased corticospinal excitability compared with FCR voluntary contraction without median nerve stimulation (p<0.05). Thus, median nerve stimulation during FCR voluntary contraction induces reciprocal changes in cortical excitability in agonist and antagonist muscles. Finally we also showed that even mental imagery of FCR voluntary contraction with median nerve stimulation induced the same reciprocal changes in cortical excitability in agonist and antagonist muscles. Our results support the use of voluntary contraction coupled with ES in neurorehabilitation therapy for patients.     

Three-Dimensional Cell Geometry Controls Excitable Membrane Signaling in Dictyostelium Cells

Phosphatidylinositol (3–5)-trisphosphate (PtdInsP3) is known to propagate as waves on the plasma membrane and is related to the membrane-protrusive activities in Dictyostelium and mammalian cells. Although there have been a few attempts to study the three-dimensional (3D) dynamics of these processes, most studies have focused on the dynamics extracted from single focal planes. However, the relation between the dynamics and 3D cell shape remains elusive because of the lack of signaling information about the unobserved part of the membrane. Here, we show that PtdInsP3 wave dynamics are directly regulated by the 3D geometry (i.e., size and shape) of the plasma membrane. By introducing an analysis method that extracts the 3D spatiotemporal activities on the entire cell membrane, we show that PtdInsP3 waves self-regulate their dynamics within the confined membrane area. This leads to changes in speed, orientation, and pattern evolution, following the underlying excitability of the signal transduction system. Our findings emphasize the role of the plasma membrane topology in reaction-diffusion-driven biological systems and indicate its importance in other mammalian systems.     

Plant- and stimulus-specific variations in remote-controlled sieve-tube occlusion

Phloem injury triggers local sieve-plate occlusion including callose-mediated constriction and protein plugging of sieve pores. In intact plants, reversible sieve-plate occlusion is induced by electric potential waves (EPWs)—accompanied by Ca²⁺-influx—as result of distant burning. Here, we present additional results which pertain to (a) the variability of EPW-profiles in relation to forisome conformation in intact Vicia faba plants and (b) the differential occlusion reactions to burning and cutting in various plant species. A correlation between stimulus perception and mode of phloem loading is discussed.Key words: callose, electrical potential waves, forisome, membrane potential, phloem transport, sieve-element occlusion, wound potentials     

Modeling K,ATP-Dependent Excitability in Pancreatic Islets

In pancreatic β-cells, K,ATP channels respond to changes in glucose to regulate cell excitability and insulin release. Confirming a high sensitivity of electrical activity to K,ATP activity, mutations that cause gain of K,ATP function cause neonatal diabetes. Our aim was to quantitatively assess the contribution of K,ATP current to the regulation of glucose-dependent bursting by reproducing experimentally observed changes in excitability when K,ATP conductance is altered by genetic manipulation. A recent detailed computational model of single cell pancreatic β-cell excitability reproduces the β-cell response to varying glucose concentrations. However, initial simulations showed that the model underrepresents the significance of K,ATP activity and was unable to reproduce K,ATP conductance-dependent changes in excitability. By altering the ATP and glucose dependence of the L-type Ca²⁺ channel and the Na-K ATPase to better fit experiment, appropriate dependence of excitability on K,ATP conductance was reproduced. Because experiments were conducted in islets, which contain cell-to-cell variability, we extended the model from a single cell to a three-dimensional model (10×10×10 cell) islet with 1000 cells. For each cell, the conductance of the major currents was allowed to vary as was the gap junction conductance between cells. This showed that single cell glucose-dependent behavior was then highly variable, but was uniform in coupled islets. The study highlights the importance of parameterization of detailed models of β-cell excitability and suggests future experiments that will lead to improved characterization of β-cell excitability and the control of insulin secretion.     

Network Bursting Dynamics in Excitatory Cortical Neuron Cultures Results from the Combination of Different Adaptive Mechanism

In the brain, synchronization among cells of an assembly is a common phenomenon, and thought to be functionally relevant. Here we used an in vitro experimental model of cell assemblies, cortical cultures, combined with numerical simulations of a spiking neural network (SNN) to investigate how and why spontaneous synchronization occurs. In order to deal with excitation only, we pharmacologically blocked GABA_Aergic transmission using bicuculline. Synchronous events in cortical cultures tend to involve almost every cell and to display relatively constant durations. We have thus named these “network spikes” (NS). The inter-NS-intervals (INSIs) proved to be a more interesting phenomenon. In most cortical cultures NSs typically come in series or bursts (“bursts of NSs”, BNS), with short (∼1 s) INSIs and separated by long silent intervals (tens of s), which leads to bimodal INSI distributions. This suggests that a facilitating mechanism is at work, presumably short-term synaptic facilitation, as well as two fatigue mechanisms: one with a short timescale, presumably short-term synaptic depression, and another one with a longer timescale, presumably cellular adaptation. We thus incorporated these three mechanisms into the SNN, which, indeed, produced realistic BNSs. Next, we systematically varied the recurrent excitation for various adaptation timescales. Strong excitability led to frequent, quasi-periodic BNSs (CV∼0), and weak excitability led to rare BNSs, approaching a Poisson process (CV∼1). Experimental cultures appear to operate within an intermediate weakly-synchronized regime (CV∼0.5), with an adaptation timescale in the 2–8 s range, and well described by a Poisson-with-refractory-period model. Taken together, our results demonstrate that the INSI statistics are indeed informative: they allowed us to infer the mechanisms at work, and many parameters that we cannot access experimentally.     

Intrinsic Islet Heterogeneity and Gap Junction Coupling Determine Spatiotemporal Ca2+ Wave Dynamics

Insulin is released from the islets of Langerhans in discrete pulses that are linked to synchronized oscillations of intracellular free calcium ([Ca²⁺]_i). Associated with each synchronized oscillation is a propagating calcium wave mediated by Connexin36 (Cx36) gap junctions. A computational islet model predicted that waves emerge due to heterogeneity in β-cell function throughout the islet. To test this, we applied defined patterns of glucose stimulation across the islet using a microfluidic device and measured how these perturbations affect calcium wave propagation. We further investigated how gap junction coupling regulates spatiotemporal [Ca²⁺]_i dynamics in the face of heterogeneous glucose stimulation. Calcium waves were found to originate in regions of the islet having elevated excitability, and this heterogeneity is an intrinsic property of islet β-cells. The extent of [Ca²⁺]_i elevation across the islet in the presence of heterogeneity is gap-junction dependent, which reveals a glucose dependence of gap junction coupling. To better describe these observations, we had to modify the computational islet model to consider the electrochemical gradient between neighboring β-cells. These results reveal how the spatiotemporal [Ca²⁺]_i dynamics of the islet depend on β-cell heterogeneity and cell-cell coupling, and are important for understanding the regulation of coordinated insulin release across the islet.     

Stress-induced mutagenesis and complex adaptation

Because mutations are mostly deleterious, mutation rates should be reduced by natural selection. However, mutations also provide the raw material for adaptation. Therefore, evolutionary theory suggests that the mutation rate must balance between adaptability—the ability to adapt—and adaptedness—the ability to remain adapted. We model an asexual population crossing a fitness valley and analyse the rate of complex adaptation with and without stress-induced mutagenesis (SIM)—the increase of mutation rates in response to stress or maladaptation. We show that SIM increases the rate of complex adaptation without reducing the population mean fitness, thus breaking the evolutionary trade-off between adaptability and adaptedness. Our theoretical results support the hypothesis that SIM promotes adaptation and provide quantitative predictions of the rate of complex adaptation with different mutational strategies.