Predicting spike timing of neocortical pyramidal neurons by simple threshold models

Neurons generate spikes reliably with millisecond precision if driven by a fluctuating current--is it then possible to predict the spike timing knowing the input? We determined parameters of an adapting threshold model using data recorded in vitro from 24 layer 5 pyramidal neurons from rat somatosensory cortex, stimulated intracellularly by a fluctuating current simulating synaptic bombardment in vivo. The model generates output spikes whenever the membrane voltage (a filtered version of the input current) reaches a dynamic threshold. We find that for input currents with large fluctuation amplitude, up to 75% of the spike times can be predicted with a precision of +/-2 ms. Some of the intrinsic neuronal unreliability can be accounted for by a noisy threshold mechanism. Our results suggest that, under random current injection into the soma, (i) neuronal behavior in the subthreshold regime can be well approximated by a simple linear filter; and (ii) most of the nonlinearities are captured by a simple threshold process.

Obesity lowers the threshold of allergic sensitization and augments airway eosinophilia in a mouse model of asthma

Clinical and epidemiological studies show a close association between obesity and the risk of asthma development. The underlying cause-effect relationship between metabolism, innate and adaptive immunity, and inflammation remains to be elucidated.

Enhanced Atlantic subpolar gyre variability through baroclinic threshold in a coarse resolution model

Direct observations, satellite measurements and paleo records reveal strong variability in the Atlantic subpolar gyre on various time scales. Here we show that variations of comparable amplitude can only be simulated in a coupled climate model in the proximity of a dynamical threshold. The threshold and the associated dynamic response is due to a positive feedback involving increased salt transport in the subpolar gyre and enhanced deep convection in its centre. A series of sensitivity experiments is performed with a coarse resolution ocean general circulation model coupled to a statistical-dynamical atmosphere model which in itself does not produce atmospheric variability. To simulate the impact of atmospheric variability, the model system is perturbed with freshwater forcing of varying, but small amplitude and multi-decadal to centennial periodicities and observational variations in wind stress. While both freshwater and wind-stress-forcing have a small direct effect on the strength of the subpolar gyre, the magnitude of the gyre's response is strongly increased in the vicinity of the threshold. Our results indicate that baroclinic self-amplification in the North Atlantic ocean can play an important role in presently observed SPG variability and thereby North Atlantic climate variability on multi-decadal scales.

Pharmacokinetics and pharmacodynamic effects of meloxicam in piglets subjected to a kaolin inflammation model

The pharmacokinetics and the analgesic, anti-inflammatory and antipyretic effects of meloxicam were investigated in a placebo controlled study in 2-week-old piglets. Inflammation was induced by a subcutaneous injection of kaolin in the left metacarpus, and 16 h later, meloxicam (0.6 mg/kg) or saline was administered intramuscularly. The absorption half-life was relatively short (0.19 h) and the elimination half-life was 2.6 h. Mechanical nociceptive threshold testing was used to evaluate the analgesic effect, but no significant effect of the meloxicam treatment was found. The skin temperature of the inflamed area increased after the kaolin injection, but no significant decrease in temperature was found after administration of meloxicam. Only limited pyresis was observed after the kaolin injection, and no significant antipyretic effect of meloxicam was found. The results indicated that this dose of meloxicam had very limited anti-inflammatory and analgesic effects in piglets.

Rufinamide attenuates mechanical allodynia in a model of neuropathic pain in the mouse and stabilizes voltage-gated sodium channel inactivated state

Background: Voltage-gated sodium channels dysregulation is important for hyperexcitability leading to pain persistence. Sodium channel blockers currently used to treat neuropathic pain are poorly tolerated. Getting new molecules to clinical use is laborious. We here propose a drug already marketed as anticonvulsant, rufinamide. Methods: We compared the behavioral effect of rufinamide to amitriptyline using the Spared Nerve Injury neuropathic pain model in mice. We compared the effect of rufinamide on sodium currents using in vitro patch clamp in cells expressing the voltage-gated sodium channel Nav1.7 isoform and on dissociated dorsal root ganglion neurons to amitriptyline and mexiletine. Results: In naive mice, amitriptyline (20 mg/kg) increased withdrawal threshold to mechanical stimulation from 1.3 (0.6–1.9) (median [95% CI]) to 2.3 g (2.2–2.5) and latency of withdrawal to heat stimulation from 13.1 (10.4–15.5) to 30.0 s (21.8–31.9), whereas rufinamide had no effect. Rufinamide and amitriptyline alleviated injury-induced mechanical allodynia for 4 h (maximal effect: 0.10 ± 0.03 g (mean ± SD) to 1.99 ± 0.26 g for rufinamide and 0.25 ± 0.22 g to 1.92 ± 0.85 g for amitriptyline). All drugs reduced peak current and stabilized the inactivated state of voltage-gated sodium channel Nav1.7, with similar effects in dorsal root ganglion neurons. Conclusions: At doses alleviating neuropathic pain, amitriptyline showed alteration of behavioral response possibly related to either alteration of basal pain sensitivity or sedative effect or both. Side-effects and drug tolerance/compliance are major problems with drugs such as amitriptyline. Rufinamide seems to have a better tolerability profile and could be a new alternative to explore for the treatment of neuropathic pain.

Methodological approach to the first and second lactate threshold in incremental cardiopulmonary exercise testing

Determination of an 'anaerobic threshold' plays an important role in the appreciation of an incremental cardiopulmonary exercise test and describes prominent changes of blood lactate accumulation with increasing workload. Two lactate thresholds are discerned during cardiopulmonary exercise testing and used for physical fitness estimation or training prescription. A multitude of different terms are, however, found in the literature describing the two thresholds. Furthermore, the term 'anaerobic threshold' is synonymously used for both, the 'first' and the 'second' lactate threshold, bearing a great potential of confusion. The aim of this review is therefore to order terms, present threshold concepts, and describe methods for lactate threshold determination using a three-phase model with reference to the historical and physiological background to facilitate the practical application of the term 'anaerobic threshold'.

Evolutionary demography of long-lived monocarpic perennials: a time-lagged integral projection model

1. The evolution of flowering strategies (when and at what size to flower) in monocarpic perennials is determined by balancing current reproduction with expected future reproduction, and these are largely determined by size-specific patterns of growth and survival. However, because of the difficulty in following long-lived individuals throughout their lives, this theory has largely been tested using short-lived species (< 5 years). 2. Here, we tested this theory using the long-lived monocarpic perennial Campanula thyrsoides which can live up to 16 years. We used a novel approach that combined permanent plot and herb chronology data from a 3-year field study to parameterize and validate integral projection models (IPMs). 3. Similar to other monocarpic species, the rosette leaves of C. thyrsoides wither over winter and so size cannot be measured in the year of flowering. We therefore extended the existing IPM framework to incorporate an additional time delay that arises because flowering demography must be predicted from rosette size in the year before flowering. 4. We found that all main demographic functions (growth, survival probability, flowering probability and fecundity) were strongly size-dependent and there was a pronounced threshold size of flowering. There was good agreement between the predicted distribution of flowering ages obtained from the IPMs and that estimated in the field. Mostly, there was good agreement between the IPM predictions and the direct quantitative field measurements regarding the demographic parameters lambda, R-0 and T. We therefore conclude that the model captures the main demographic features of the field populations. 5. Elasticity analysis indicated that changes in the survival and growth function had the largest effect (c. 80%) on lambda and this was considerably larger than in short-lived monocarps. We found only weak selection pressure operating on the observed flowering strategy which was close to the predicted evolutionary stable strategy. 6. Synthesis. The extended IPM accurately described the demography of a long-lived monocarpic perennial using data collected over a relatively short period. We could show that the evolution of flowering strategies in short- and long-lived monocarps seem to follow the same general rules but with a longevity-related emphasis on survival over fecundity.

Arsenic volatilization in model anaerobic biogas digesters

Arsenic is a class 1 non-threshold carcinogen which is highly ubiquitous. Arsenic undergoes many different transformations (biotic or abiotic) between and within environmental compartments, leading to a number of different chemical species possessing different properties and toxicities. One specific transformation is As biotic volatilization which is coupled with As biomethylation and has been scarcely studied due to inherent sampling issues. Arsenic methylation/volatilization is also linked with methanogenesis and occurs in anaerobic environments. In China, rice straw and animal manure are very often used to produce biogas and both can contain high amounts of As, especially if the rice is grown in areas with heavy mining or smelting industries and if Roxarsone is fed to the animals. Roxarsone is an As-containing drug which is widely used in China to control coccidian intestinal parasites, to improve feed efficiency and to promote rapid growth. Previous work has shown that this compound degrades to inorganic As under anaerobic conditions. In this study the focus is on biotic transformations of As in small microcosms designed as biogas digester models (BDMs) using recently validated As traps, thus, enabling direct quantification and identification of volatile As species. It is shown that although there was a loss of soluble As in the BDMs, their conditions favored biomethylation. All reactors produced volatile As, especially the monomethylarsonic acid spiked ones with 413 ± 148 ng As (mean ± SD, n = 3) which suggest that the first methylation step, from inorganic As, is a limiting factor. The most abundant species was trimethylarsine, but the toxic arsine was present in the headspace of most of the BDMs. The results suggest that volatile As species should be monitored in biogas digesters in order to assess risks to humans working in biogas plants and those utilizing the biogas.

Do different anesthesia regimes affect hippocampal apoptosis and neurologic deficits in a rodent cardiac arrest model?

Background Different anesthesia regimes are commonly used in experimental models of cardiac arrest, but the effects of various anesthetics on clinical outcome parameters are unknown. We conducted a study in which we subjected rats to cardiac arrest under medetomidine/ketamine or sevoflurane/fentanyl anesthesia. Methods Asystolic cardiac arrest for 8 minutes was induced in 73 rats with a mixture of potassium chloride and esmolol. Daily behavioral and neurological examination included the open field test (OFT), the tape removal test (TRT) and a neurodeficit score (NDS). Animals were randomized for sacrifice on day 2 or day 5 and brains were harvested for histology in the hippocampus cornus ammonis segment CA1. The inflammatory markers IL-6, TNF-α, MCP-1 and MIP-1α were assessed in cerebrospinal fluid (CSF). Proportions of survival were tested with the Fisher’s exact test, repeated measurements were assessed with the Friedman’s test; the baseline values were tested using Mann–Whitney U test and the difference of results of repeated measures were compared. Results In 31 animals that survived beyond 24 hours neither OFT, TRT nor NDS differed between the groups; histology was similar on day 2. On day 5, significantly more apoptosis in the CA1 segment of the hippocampus was found in the sevoflurane/fentanyl group. MCP-1 was higher on day 5 in the sevoflurane/fentanyl group (p = 0.04). All other cyto- and chemokines were below detection threshold. Conclusion In our cardiac arrest model neurological function was not influenced by different anesthetic regimes; in contrast, anesthesia with sevoflurane/fentanyl results in increased CSF inflammation and histologic damage at day 5 post cardiac arrest.

Multi-Environment Model Estimation for Motility Analysis of Caernorhabditis elegans

The nematode Caenorhabditis elegans is a well-known model organism used to investigate fundamental questions in biology. Motility assays of this small roundworm are designed to study the relationships between genes and behavior. Commonly, motility analysis is used to classify nematode movements and characterize them quantitatively. Over the past years, C. elegans' motility has been studied across a wide range of environments, including crawling on substrates, swimming in fluids, and locomoting through microfluidic substrates. However, each environment often requires customized image processing tools relying on heuristic parameter tuning. In the present study, we propose a novel Multi-Environment Model Estimation (MEME) framework for automated image segmentation that is versatile across various environments. The MEME platform is constructed around the concept of Mixture of Gaussian (MOG) models, where statistical models for both the background environment and the nematode appearance are explicitly learned and used to accurately segment a target nematode. Our method is designed to simplify the burden often imposed on users; here, only a single image which includes a nematode in its environment must be provided for model learning. In addition, our platform enables the extraction of nematode ‘skeletons’ for straightforward motility quantification. We test our algorithm on various locomotive environments and compare performances with an intensity-based thresholding method. Overall, MEME outperforms the threshold-based approach for the overwhelming majority of cases examined. Ultimately, MEME provides researchers with an attractive platform for C. elegans' segmentation and ‘skeletonizing’ across a wide range of motility assays.