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Psychedelic drugs are under active consideration for clinical use and have generated significant interest for their potential as anti-nociceptive treatments for chronic pain, and for addressing conditions like depression, frequently co-morbid with pain. This review primarily explores the utility of preclinical animal models in investigating the potential of psilocybin as an anti-nociceptive agent. Initial studies involving psilocybin in animal models of neuropathic and inflammatory pain are summarised, alongside areas where further research is needed. The potential mechanisms of action, including targeting serotonergic pathways through the activation of 5-HT 2A receptors at both spinal and central levels, as well as neuroplastic actions that improve functional connectivity in brain regions involved in chronic pain, are considered. Current clinical aspects and the translational potential of psilocybin from animal models to chronic pain patients are reviewed. Also discussed is psilocybin's profile as an ideal anti-nociceptive agent, with a wide range of effects against chronic pain and its associated inflammatory or emotional components., (© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Natural products (NPs) have long been used as a rich source of bioactive compounds for drug development. Recent technological advancements have revitalised natural products research as evidenced by increased publications in this field. In this editorial review, we highlight key points from the 2020 British Journal of Pharmacology (BJP) practical guide, which outlines standards for natural products research reports, and provide papers published in BJP between years 2020 to 2023 that demonstrate adherence to these guidelines. Looking ahead, we discuss the potential of chemical proteomics approaches to elucidate natural products mechanisms of action and identify therapeutic targets for future research. By fostering innovation, we aim to advance natural products research and contribute to the development of novel therapeutics that will have a significant impact on healthcare., (© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

How do we capture the breadth of behavior in animal movement, from rapid body twitches to aging? Using high-resolution videos of the nematode worm Caenorhabditis elegans , we show that a single dynamics connects posture-scale fluctuations with trajectory diffusion and longer-lived behavioral states. We take short posture sequences as an instantaneous behavioral measure, fixing the sequence length for maximal prediction. Within the space of posture sequences, we construct a fine-scale, maximum entropy partition so that transitions among microstates define a high-fidelity Markov model, which we also use as a means of principled coarse-graining. We translate these dynamics into movement using resistive force theory, capturing the statistical properties of foraging trajectories. Predictive across scales, we leverage the longest-lived eigenvectors of the inferred Markov chain to perform a top-down subdivision of the worm's foraging behavior, revealing both "runs-and-pirouettes" as well as previously uncharacterized finer-scale behaviors. We use our model to investigate the relevance of these fine-scale behaviors for foraging success, recovering a trade-off between local and global search strategies., Competing Interests: Competing interests statement:The authors declare no competing interest.

In 2023, seventy novel drugs received market authorization for the first time in either Europe (by the EMA and the MHRA) or in the United States (by the FDA). Confirming a steady recent trend, more than half of these drugs target rare diseases or intractable forms of cancer. Thirty drugs are categorized as "first-in-class" (FIC), illustrating the quality of research and innovation that drives new chemical entity discovery and development. We succinctly describe the mechanism of action of most of these FIC drugs and discuss the therapeutic areas covered, as well as the chemical category to which these drugs belong. The 2023 novel drug list also demonstrates an unabated emphasis on polypeptides (recombinant proteins and antibodies), Advanced Therapy Medicinal Products (gene and cell therapies) and RNA therapeutics, including the first-ever approval of a CRISPR-Cas9-based gene-editing cell therapy., (© 2024 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Nanobodies are recombinant antigen-specific single domain antibodies (VHHs) derived from the heavy chain-only subset of camelid immunoglobulins. Their small molecular size, facile expression, high affinity, and stability have combined to make them unique targeting reagents with numerous applications in the biomedical sciences. From our work in producing nanobodies to over sixty different proteins, we present a standardised workflow for nanobody discovery from llama immunisation, library building, panning, and small-scale expression for prioritisation of binding clones. In addition, we introduce our suites of mammalian and bacterial vectors, which can be used to functionalise selected nanobodies for various applications such as in imaging and purification. Key features • Standardise the process of building nanobody libraries and finding nanobody binders so that it can be repeated in any lab with reasonable equipment. • Introduce two suites of vectors to functionalise nanobodies for production in either bacterial or mammalian cells., Competing Interests: Competing interestsThe authors declare that they have no competing interests with respect to the work described., (©Copyright : © 2024 The Authors; This is an open access article under the CC BY-NC license.)

Isolating slower dynamics from fast fluctuations has proven remarkably powerful, but how do we proceed from partial observations of dynamical systems for which we lack underlying equations? Here, we construct maximally predictive states by concatenating measurements in time, partitioning the resulting sequences using maximum entropy, and choosing the sequence length to maximize short-time predictive information. Transitions between these states yield a simple approximation of the transfer operator, which we use to reveal timescale separation and long-lived collective modes through the operator spectrum. Applicable to both deterministic and stochastic processes, we illustrate our approach through partial observations of the Lorenz system and the stochastic dynamics of a particle in a double-well potential. We use our transfer operator approach to provide a new estimator of the Kolmogorov-Sinai entropy, which we demonstrate in discrete and continuous-time systems, as well as the movement behavior of the nematode worm C. elegans.

The GluR3 subunit of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) has been identified as a target for autoantibodies (Aabs) in autoimmune encephalopathy and other diseases. Recent studies have proposed mechanisms by which these Aabs act, but their exact role in neuronal excitability is yet to be established. Patient Aabs have been shown to bind to specific regions within the GluR3 subunit. GLUR3B peptides were designed based on described (ELISA) immunogenic epitopes for Aabs and an immunisation strategy was used to generate novel anti-AMPAR Aabs. Target-specific binding and specificity of affinity-purified anti-AMPAR Aabs was confirmed using enzyme-linked immunosorbent assay, immunocytochemistry and Western blot. Functional anti-AMPAR Aab effects were determined on excitatory postsynaptic currents (EPSCs) from primary hippocampal neurons using whole-cell patch-clamp electrophysiology. Acute (10 or 30 min) or longer-term (24 h) application of anti-AMPAR Aabs caused a significant reduction in the mean frequency of spontaneous and miniature EPSCs in hippocampal neurons. Our data demonstrate that anti-AMPAR Aabs targeting peptides linked to auto-immune diseases mediate inhibitory effects on neuronal excitability at the synaptic level, such effects may lead to disruption of the excitatory/inhibitory balance at a network level.

The COVID-19 pandemic caused by SARS-CoV2 has raised several important health concerns, not least increased mortality and morbidity. SARS-CoV2 can infect the central nervous system via hematogenous or transneuronal routes, acting through different receptors including ACE2, DPP4, and neuropilin 1 and cause several issues, including the focus here, cerebellitis. The cerebellum is an essential part of the CNS located adjacent to the brainstem with a complex micro and macroscopic structure. The cerebellum plays several physiological roles, such as coordination, cognition, and executive functioning. Damage to the cerebellum can lead to incoordination and ataxia. In our narrative review, we searched different databases from 2021 to 2022 with the keywords cerebellum and COVID-19; 247 studies were identified and reviewed, focusing on clinical studies and excluding non-clinical studies; 56 studies were finally included for analysis. SARS-CoV2 infection of the cerebellum can be seen to be assessed through many methods such as MRI, PET, CT, postmortem studies, and histological findings. These methodological studies have demonstrated that cerebellar infection with COVID-19 can bring about several sequelae: thrombosis, microbleed, hemorrhage, stroke, autoantibody production, ataxia, and widespread inflammation in the cerebellum. Such central effects are likely to exacerbate the known multiorgan effects of SARS-CoV2 and should also be considered as part of disease prognosis.

Cav2.2 channels are key regulators of presynaptic Ca 2+ influx and their dysfunction and/or aberrant regulation has been implicated in many disease states; however, the nature of their involvement in Alzheimer's disease (AD) is less clear. In this short communication, we show that recombinant hCav2.2/b 1b /a 2 d 1 channels are modulated by human synthetic AD-related protofibrillar amyloid beta Ab 1-42 peptides. Structural studies revealed a time-dependent increase in protofibril length, with the majority of protofibrils less than 100 nm at 24 h, while at 48 h, the majority were longer than 100 nm. Cav2.2 modulation by Ab 1-42 was different between a 'low' (100 nM) and 'high' (1 µM) concentration in terms of distinct effects on individual biophysical parameters. A concentration of 100 nM Ab 1-42 caused no significant changes in the measured biophysical properties of Cav2.2 currents. In contrast, 1 µM Ab 1-42 caused an inhibitory decrease in the current density (pA/pF) and maximum conductance (Gmax), and a depolarizing shift in the slope factor (k). These data highlight a differential modulation of Cav2.2 channels by the Ab 1-42 peptide. Discrete changes in the presynaptic Ca 2+ flux have been reported to occur at an early stage of AD; therefore, this study reveals a potential mechanistic link between amyloid accumulation and Ca v 2.2 channel modulation.

The α 2 δ auxiliary subunits of voltage-gated calcium channels (VGCC) were traditionally regarded as modulators of biophysical channel properties. In recent years, channel-independent functions of these subunits, such as involvement in synapse formation, have been identified. In the central nervous system, α 2 δ isoforms 1, 2, and 3 are strongly expressed, regulating glutamatergic synapse formation by a presynaptic mechanism. Although the α 2 δ-4 isoform is predominantly found in the retina with very little expression in the brain, it was recently linked to brain functions. In contrast, Cachd1, a novel α 2 δ-like protein, shows strong expression in brain, but its function in neurons is not yet known. Therefore, we aimed to investigate the presynaptic functions of α 2 δ-4 and Cachd1 by expressing individual proteins in cultured hippocampal neurons. Both α 2 δ-4 and Cachd1 are expressed in the presynaptic membrane and could rescue a severe synaptic defect present in triple knockout/knockdown neurons that lacked the α 2 δ-1-3 isoforms (α 2 δ TKO/KD). This observation suggests that presynaptic localization and the regulation of synapse formation in glutamatergic neurons is a general feature of α 2 δ proteins. In contrast to this redundant presynaptic function, α 2 δ-4 and Cachd1 differentially regulate the abundance of presynaptic calcium channels and the amplitude of presynaptic calcium transients. These functional differences may be caused by subtle isoform-specific differences in α 1 -α 2 δ protein-protein interactions, as revealed by structural homology modelling. Taken together, our study identifies both α 2 δ-4 and Cachd1 as presynaptic regulators of synapse formation, differentiation, and calcium channel functions that can at least partially compensate for the loss of α 2 δ-1-3. Moreover, we show that regulating glutamatergic synapse formation and differentiation is a critical and surprisingly redundant function of α 2 δ and Cachd1.

While stress reactions can emerge long after the triggering event, it remains elusive how they emerge after a protracted, seemingly stress-free period during which stress incubates. Here, we study the behavioral development in mice isolated after observing an aggressive encounter inflicted upon their pair-housed partners. We developed a spatially resolved fine-scale behavioral analysis and applied it to standard behavioral tests. It reveals that the seemingly sudden behavioral changes developed gradually. These behavioral changes were not observed if the aggressive encounter happened to a stranger mouse, suggesting that social bonding is a prerequisite for stress incubation in this paradigm. This finding was corroborated by hemisphere-specific morphological changes in cortex regions centering at the anterior cingulate cortex, a cognitive and emotional center. Our non-invasive analytical methods to capture informative behavioral details may have applications beyond laboratory animals., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lee, Stephens and Kuhn.)

An important model system for understanding genes, neurons and behavior, the nematode worm C. elegans naturally moves through a variety of complex postures, for which estimation from video data is challenging. We introduce an open-source Python package, WormPose, for 2D pose estimation in C. elegans, including self-occluded, coiled shapes. We leverage advances in machine vision afforded from convolutional neural networks and introduce a synthetic yet realistic generative model for images of worm posture, thus avoiding the need for human-labeled training. WormPose is effective and adaptable for imaging conditions across worm tracking efforts. We quantify pose estimation using synthetic data as well as N2 and mutant worms in on-food conditions. We further demonstrate WormPose by analyzing long (∼ 8 hour), fast-sampled (∼ 30 Hz) recordings of on-food N2 worms to provide a posture-scale analysis of roaming/dwelling behaviors., Competing Interests: The authors have declared that no competing interests exist.

Honeybee swarms are a landmark example of collective behavior. To become a coherent swarm, bees locate their queen by tracking her pheromones. But how can distant individuals exploit these chemical signals, which decay rapidly in space and time? Here, we combine a behavioral assay with the machine vision detection of organism location and scenting (pheromone propagation via wing fanning) behavior to track the search and aggregation dynamics of the honeybee Apis mellifera L. We find that bees collectively create a scenting-mediated communication network by arranging in a specific spatial distribution where there is a characteristic distance between individuals and directional signaling away from the queen. To better understand such a flow-mediated directional communication strategy, we developed an agent-based model where bee agents obeying simple, local behavioral rules exist in a flow environment in which the chemical signals diffuse and decay. Our model serves as a guide to exploring how physical parameters affect the collective scenting behavior and shows that increased directional bias in scenting leads to a more efficient aggregation process that avoids local equilibrium configurations of isotropic (nondirectional and axisymmetric) communication, such as small bee clusters that persist throughout the simulation. Our results highlight an example of extended classical stigmergy: Rather than depositing static information in the environment, individual bees locally sense and globally manipulate the physical fields of chemical concentration and airflow., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)

From cells in tissue, to bird flocks, to human crowds, living systems display a stunning variety of collective behaviors. Yet quantifying such phenomena first requires tracking a significant fraction of the group members in natural conditions, a substantial and ongoing challenge. We present a comprehensive, computational method for tracking an entire colony of the honey bee Apis mellifera using high-resolution video on a natural honeycomb background. We adapt a convolutional neural network (CNN) segmentation architecture to automatically identify bee and brood cell positions, body orientations and within-cell states. We achieve high accuracy (~10% body width error in position, ~10° error in orientation, and true positive rate > 90%) and demonstrate months-long monitoring of sociometric colony fluctuations. These fluctuations include ~24 h cycles in the counted detections, negative correlation between bee and brood, and nightly enhancement of bees inside comb cells. We combine detected positions with visual features of organism-centered images to track individuals over time and through challenging occluding events, recovering ~79% of bee trajectories from five observation hives over 5 min timespans. The trajectories reveal important individual behaviors, including waggle dances and crawling inside comb cells. Our results provide opportunities for the quantitative study of collective bee behavior and for advancing tracking techniques of crowded systems.

SUMOylation is an important post-translational modification process involving covalent attachment of SUMO (Small Ubiquitin-like MOdifier) protein to target proteins. Here, we investigated the potential for SUMO-1 protein to modulate the function of the Ca V 2.2 (N-type) voltage-gated calcium channel (VGCC), a protein vital for presynaptic neurotransmitter release. Co-expression of SUMO-1, but not the conjugation-deficient mutant SUMO-1ΔGG, increased heterologously-expressed Ca V 2.2 Ca 2+ current density, an effect potentiated by the conjugating enzyme Ubc9. Expression of sentrin-specific protease (SENP)-1 or Ubc9 alone, had no effect on recombinant Ca V 2.2 channels. Co-expression of SUMO-1 and Ubc9 caused an increase in whole-cell maximal conductance (G max ) and a hyperpolarizing shift in the midpoint of activation (V 1/2 ). Mutation of all five Ca V 2.2 lysine residues to arginine within the five highest probability (>65 %) SUMOylation consensus motifs (SCMs) (construct Ca V 2.2-Δ5KR), produced a loss-of-function mutant. Mutagenesis of selected individual lysine residues identified K394, but not K951, as a key residue for SUMO-1-mediated increase in Ca V 2.2 Ca 2+ current density. In synaptically-coupled superior cervical ganglion (SCG) neurons, SUMO-1 protein was distributed throughout the cell body, axons and dendrites and presumptive presynaptic terminals, whilst SUMO-1ΔGG protein was largely confined to the cell body, in particular, the nucleus. SUMO-1 expression caused increases in paired excitatory postsynaptic potential (EPSP) ratio at short (20-120 ms) inter-stimuli intervals in comparison to SUMO-1ΔGG, consistent with an increase in residual presynaptic Ca 2+ current and an increase in release probability of synaptic vesicles. Together, these data provide evidence for Ca V 2.2 VGCCs as novel targets for SUMOylation pathways., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Electrophysiology is an essential tool aiding the study of the functions and dysfunctions of electrically excitable cells and their networks. The patch clamp method is a refined electrophysiological technique that can directly measure the membrane potential and/or the amount of current passing across the cell membrane. The patch clamp technique is also incredibly versatile and can be used in a variety of different configurations to study a range of properties, from spontaneous cell firing activity in native tissue to the activation and/or deactivation kinetics of individual channels expressed in recombinant cell lines. In this chapter we give an overview of patch clamping and how the different configurations can be set up and applied to electrophysiological research.

In recent years, there has been a growing appreciation by regulatory authorities that cannabis-based medicines can play a useful role in disease therapy. Although often conflagrated by proponents of recreational use, the legislative rescheduling of cannabis-derived compounds, such as cannabidiol (CBD), has been associated with the steady increase in the pursuit of use of medicinal cannabis. One key driver in this interest has been the scientific demonstration of efficacy and safety of CBD in randomised, placebo-controlled clinical trials in children and young adults with difficult-to-treat epilepsies, which has encouraged increasing numbers of human trials of CBD for other indications and in other populations. The introduction of CBD as the medicine Epidiolex in the United States (in 2018) and as Epidyolex in the European Union (in 2019) as the first cannabis-derived therapeutic for the treatment of seizures was underpinned by preclinical research performed at the University of Reading. This work was awarded the British Pharmacological Society Sir James Black Award for Contributions to Drug Discovery 2019 and is discussed in the following review article., (© 2020 The British Pharmacological Society.)

Time-lapse microscopy is routinely used to follow cells within organoids, allowing direct study of division and differentiation patterns. There is an increasing interest in cell tracking in organoids, which makes it possible to study their growth and homeostasis at the single-cell level. As tracking these cells by hand is prohibitively time consuming, automation using a computer program is required. Unfortunately, organoids have a high cell density and fast cell movement, which makes automated cell tracking difficult. In this work, a semi-automated cell tracker has been developed. To detect the nuclei, we use a machine learning approach based on a convolutional neural network. To form cell trajectories, we link detections at different time points together using a min-cost flow solver. The tracker raises warnings for situations with likely errors. Rapid changes in nucleus volume and position are reported for manual review, as well as cases where nuclei divide, appear and disappear. When the warning system is adjusted such that virtually error-free lineage trees can be obtained, still less than 2% of all detected nuclei positions are marked for manual analysis. This provides an enormous speed boost over manual cell tracking, while still providing tracking data of the same quality as manual tracking., Competing Interests: The authors have declared that no competing interests exist.

We have previously reported the synthesis of a poly(ethylene glycol)-haloperidol (PEG-haloperidol) conjugate that retained affinity for its target D 2 receptor and was stable in simulated physiological conditions. We hypothesised that this polymer-drug conjugate would localise haloperidol's activity either centrally or peripherally, dependent on the location of administration, due to the polymer preventing penetration through the blood-brain barrier (BBB). Herein, we validate this hypothesis using in vitro and in vivo studies. We first demonstrate, via a [ 35 S]GTPγS-binding assay, that drug activity is retained after conjugation to the polymer, supportive of retention of effective therapeutic ability. Specifically, the PEG-haloperidol conjugate (at 10 and 100 nM) was able to significantly inhibit dopamine-induced G-protein activation via D 2 receptors, albeit with a loss of potency compared to the free haloperidol (~18-fold at 10 nM). This loss of potency was further probed and rationalised using molecular docking experiments, which indicated that conjugated haloperidol can still bind to the D 2 receptors, albeit with a flipped orientation in the binding pocket within the receptor, which may explain the reduced activity. Finally, rat catalepsy studies confirmed the restricted permeation of the conjugate through the BBB in vivo. Rats treated intravenously with free haloperidol became cataleptic, whereas normal behaviour was observed in rats that received the PEG-haloperidol conjugate, suggesting that conjugation can effectively prevent unwanted central effects. Taken together these results demonstrate that conjugating small molecules to polymers is effective at prohibiting penetration of the drug through the BBB and is a valid targeting strategy for drugs to facilitate peripheral (or central) effects without inducing side effects in other compartments., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The reliable detection of environmental molecules in the presence of noise is an important cellular function, yet the underlying computational mechanisms are not well understood. We introduce a model of two interacting sensors which allows for the principled exploration of signal statistics, cooperation strategies and the role of energy consumption in optimal sensing, quantified through the mutual information between the signal and the sensors. Here we report that in general the optimal sensing strategy depends both on the noise level and the statistics of the signals. For joint, correlated signals, energy consuming (nonequilibrium), asymmetric couplings result in maximum information gain in the low-noise, high-signal-correlation limit. Surprisingly we also find that energy consumption is not always required for optimal sensing. We generalise our model to incorporate time integration of the sensor state by a population of readout molecules, and demonstrate that sensor interaction and energy consumption remain important for optimal sensing.

A quantitative understanding of organism-level behaviour requires predictive models that can capture the richness of behavioural phenotypes, yet are simple enough to connect with underlying mechanistic processes. Here, we investigate the motile behaviour of nematodes at the level of their translational motion on surfaces driven by undulatory propulsion. We broadly sample the nematode behavioural repertoire by measuring motile trajectories of the canonical laboratory strain Caenorhabditis elegans N2 as well as wild strains and distant species. We focus on trajectory dynamics over time scales spanning the transition from ballistic (straight) to diffusive (random) movement and find that salient features of the motility statistics are captured by a random walk model with independent dynamics in the speed, bearing and reversal events. We show that the model parameters vary among species in a correlated, low-dimensional manner suggestive of a common mode of behavioural control and a trade-off between exploration and exploitation. The distribution of phenotypes along this primary mode of variation reveals that not only the mean but also the variance varies considerably across strains, suggesting that these nematode lineages employ contrasting 'bet-hedging' strategies for foraging.

Large conductance, Ca 2+ -activated K + (BK Ca ) channels are widely expressed in the central nervous system, where they regulate action potential duration, firing frequency and consequential neurotransmitter release. Moreover, drug action on, mutations to, or changes in expression levels of BK Ca can modulate neuronal hyperexcitability. Amongst other potential mechanisms of action, cannabinoid compounds have recently been reported to activate BK Ca channels. Here, we examined the effects of the cannabinoid-like compound (R,Z)-3-(6-(dimethylamino)-6-oxohex-1-en-1-yl)-N-(1-hydroxypropan-2-yl) benzamide (VSN16R) at CA1 pyramidal neurons in hippocampal ex vivo brain slices using current clamp electrophysiology. We also investigated effects of the BK Ca channel blockers iberiotoxin (IBTX) and the novel 7-pra-martentoxin (7-Pra-MarTx) on VSN16R action. VSN16R (100 μM) increased first and second fast after-hyperpolarization (fAHP) amplitude, decreased first and second inter spike interval (ISI) and shortened first action potential (AP) width under high frequency stimulation protocols in mouse hippocampal pyramidal neurons. IBTX (100 nM) decreased first fAHP amplitude, increased second ISI and broadened first and second AP width under high frequency stimulation protocols; IBTX also broadened first and second AP width under low frequency stimulation protocols. IBTX blocked effects of VSN16R on fAHP amplitude and ISI. 7-Pra-MarTx (100 nM) had no significant effects on fAHP amplitude and ISI but, unlike IBTX, shortened first and second AP width under high frequency stimulation protocols; 7-Pra-MarTx also shortened second AP width under low frequency stimulation protocols. However, in the presence of 7-Pra-MarTx, VSN16R retained some effects on AP waveform under high frequency stimulation protocols; moreover, VSN16R effects were revealed under low frequency stimulation protocols. These findings demonstrate that VSN16R has effects in native hippocampal neurons consistent with its causing an increase in initial firing frequency via activation of IBTX-sensitive BK Ca channels. The differential pharmacological effects described suggest that VSN16R may differentially target BK Ca channel subtypes.

Background and Purpose: Numerous claims are made for cannabis' therapeutic utility upon human seizures, but concerns persist about risks. A potential confounder is the presence of both Δ 9 -tetrahydrocannabinol (THC), variously reported to be pro- and anticonvulsant, and cannabidiol (CBD), widely confirmed as anticonvulsant. Therefore, we investigated effects of prolonged exposure to different THC/CBD cannabis extracts on seizure activity and associated measures of endocannabinoid (eCB) system signalling., Experimental Approach: Cannabis extract effects on in vivo neurological and behavioural responses, and on bioanalyte levels, were measured in rats and dogs. Extract effects on seizure activity were measured using electroencephalography telemetry in rats. eCB signalling was also investigated using radioligand binding in cannabis extract-treated rats and treatment-naïve rat, mouse, chicken, dog and human tissue., Key Results: Prolonged exposure to cannabis extracts caused spontaneous, generalized seizures, subserved by epileptiform discharges in rats, but not dogs, and produced higher THC, but lower 11-hydroxy-THC (11-OH-THC) and CBD, plasma concentrations in rats versus dogs. In the same rats, prolonged exposure to cannabis also impaired cannabinoid type 1 receptor (CB 1 receptor)-mediated signalling. Profiling CB 1 receptor expression, basal activity, extent of activation and sensitivity to THC suggested interspecies differences in eCB signalling, being more pronounced in a species that exhibited cannabis extract-induced seizures (rat) than one that did not (dog)., Conclusions and Implications: Sustained cannabis extract treatment caused differential seizure, behavioural and bioanalyte levels between rats and dogs. Supporting radioligand binding data suggest species differences in eCB signalling. Interspecies variations may have important implications for predicting cannabis-induced convulsions from animal models., Linked Articles: This article is part of a themed section on 8 th European Workshop on Cannabinoid Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.10/issuetoc., (© 2018 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

The dynamics of complex systems generally include high-dimensional, nonstationary, and nonlinear behavior, all of which pose fundamental challenges to quantitative understanding. To address these difficulties, we detail an approach based on local linear models within windows determined adaptively from data. While the dynamics within each window are simple, consisting of exponential decay, growth, and oscillations, the collection of local parameters across all windows provides a principled characterization of the full time series. To explore the resulting model space, we develop a likelihood-based hierarchical clustering, and we examine the eigenvalues of the linear dynamics. We demonstrate our analysis with the Lorenz system undergoing stable spiral dynamics and in the standard chaotic regime. Applied to the posture dynamics of the nematode Caenorhabditis elegans , our approach identifies fine-grained behavioral states and model dynamics which fluctuate about an instability boundary, and we detail a bifurcation in a transition from forward to backward crawling. We analyze whole-brain imaging in C. elegans and show that global brain dynamics is damped away from the instability boundary by a decrease in oxygen concentration. We provide additional evidence for such near-critical dynamics from the analysis of electrocorticography in monkey and the imaging of a neural population from mouse visual cortex at single-cell resolution., (Copyright © 2019 the Author(s). Published by PNAS.)

The putative cache (Ca 2+ channel and chemotaxis receptor) domain containing 1 (CACHD1) protein has predicted structural similarities to members of the α2δ voltage-gated Ca 2+ channel auxiliary subunit family. CACHD1 mRNA and protein were highly expressed in the male mammalian CNS, in particular in the thalamus, hippocampus, and cerebellum, with a broadly similar tissue distribution to Ca V 3 subunits, in particular Ca V 3.1. In expression studies, CACHD1 increased cell-surface localization of Ca V 3.1, and these proteins were in close proximity at the cell surface, consistent with the formation of CACHD1-Ca V 3.1 complexes. In functional electrophysiological studies, coexpression of human CACHD1 with Ca V 3.1, Ca V 3.2, and Ca V 3.3 caused a significant increase in peak current density and corresponding increases in maximal conductance. By contrast, α2δ-1 had no effect on peak current density or maximal conductance in Ca V 3.1, Ca V 3.2, or Ca V 3.3. A comparison of CACHD1-mediated increases in Ca V 3.1 current density and gating currents revealed an increase in channel open probability. In hippocampal neurons from male and female embryonic day 19 rats, CACHD1 overexpression increased Ca V 3-mediated action potential firing frequency and neuronal excitability. These data suggest that CACHD1 is structurally an α2δ-like protein that functionally modulates Ca V 3 voltage-gated calcium channel activity. SIGNIFICANCE STATEMENT This is the first study to characterize the Ca 2+ channel and chemotaxis receptor domain containing 1 (CACHD1) protein. CACHD1 is widely expressed in the CNS, in particular in the thalamus, hippocampus, and cerebellum. CACHD1 distribution is similar to that of low voltage-activated (Ca V 3, T-type) calcium channels, in particular to Ca V 3.1, a protein that regulates neuronal excitability and is a potential therapeutic target in conditions such as epilepsy and pain. CACHD1 is structurally an α2δ-like protein that functionally increases Ca V 3 calcium current. CACHD1 increases the presence of Ca V 3.1 at the cell surface, forms complexes with Ca V 3.1 at the cell surface, and causes an increase in channel open probability. In hippocampal neurons, CACHD1 causes increases in neuronal firing. Thus, CACHD1 represents a novel protein that modulates Ca V 3 activity., (Copyright © 2018 the authors 0270-6474/18/389186-16$15.00/0.)

One of the most interesting but tenebrous parts of the bipolar disorder (BD) story is the switch between (hypo)mania and depression, which can give bipolar patients a thrilling, but somewhat perilous, 'ride'. Numerous studies have pointed out that there are some recognizable differences (either state-dependent or state-independent) in several brain regions of people with BD, including components of the brain's reward system. Understanding the underpinning mechanisms of high and low mood statuses in BD has potential, not only for the development of highly specific and selective pharmaceutical agents, but also for better treatment approaches and psychological interventions to manage BD and, thus, give patients a safer ride. Herein, we review evidence that supports involvement of the reward system in the pathophysiology of mood swings, with the main focus on the mesocorticolimbic dopaminergic neural circuitry. Principally using findings from neuroimaging studies, we aim to signpost readers as to how mood alterations may affect different areas of the reward system and how antipsychotic drugs can influence the activity of these brain areas. Finally, we critically evaluate the hypothesis that the mesocorticolimbic dopamine reward system may act as a functional rheostat for different mood states.

Linked Articles: This article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc., (© 2018 The British Pharmacological Society.)

A deterministic population dynamics model involving birth and death for a two-species system, comprising a wild-type and more resistant species competing via logistic growth, is subjected to two distinct stress environments designed to mimic those that would typically be induced by temporal variation in the concentration of a drug (antibiotic or chemotherapeutic) as it permeates through the population and is progressively degraded. Different treatment regimes, involving single or periodical doses, are evaluated in terms of the minimal population size (a measure of the extinction probability), and the population composition (a measure of the selection pressure for resistance or tolerance during the treatment). We show that there exist timescales over which the low-stress regime is as effective as the high-stress regime, due to the competition between the two species. For multiple periodic treatments, competition can ensure that the minimal population size is attained during the first pulse when the high-stress regime is short, which implies that a single short pulse can be more effective than a more protracted regime. Our results suggest that when the duration of the high-stress environment is restricted, a treatment with one or multiple shorter pulses can produce better outcomes than a single long treatment. If ecological competition is to be exploited for treatments, it is crucial to determine these timescales, and estimate for the minimal population threshold that suffices for extinction. These parameters can be quantified by experiment.

Small ubiquitin-like modifier (SUMO) conjugation (or SUMOylation) is a post-translational protein modification implicated in alterations to protein expression, localization and function. Despite a number of nuclear roles for SUMO being well characterized, this process has only started to be explored in relation to membrane proteins, such as ion channels. Calcium ion (Ca 2+ ) signalling is crucial for the normal functioning of cells and is also involved in the pathophysiological mechanisms underlying relevant neurological and cardiovascular diseases. Intracellular Ca 2+ levels are tightly regulated; at rest, most Ca 2+ is retained in organelles, such as the sarcoplasmic reticulum, or in the extracellular space, whereas depolarization triggers a series of events leading to Ca 2+ entry, followed by extrusion and reuptake. The mechanisms that maintain Ca 2+ homoeostasis are candidates for modulation at the post-translational level. Here, we review the effects of protein SUMOylation, including Ca 2+ channels, their proteome and other proteins associated with Ca 2+ signalling, on vital cellular functions, such as neurotransmission within the central nervous system (CNS) and in additional systems, most prominently here, in the cardiac system., Competing Interests: The authors declare that there are no competing interests associated with the manuscript., (© 2017 The Author(s).)

With the advent of online networks, societies have become substantially more interconnected with individual members able to easily both maintain and modify their own social links. Here, we show that active network maintenance exposes agents to confirmation bias, the tendency to confirm one's beliefs, and we explore how this bias affects collective opinion formation. We introduce a model of binary opinion dynamics on a complex, fluctuating network with stochastic rewiring and we analyze these dynamics in the mean-field limit of large networks and fast link rewiring. We show that confirmation bias induces a segregation of individuals with different opinions and stabilizes the consensus state. We further show that bias can have an unusual, nonmonotonic effect on the time to consensus and this suggests a novel avenue for large-scale opinion manipulation.

We exploit the reduced space of C. elegans postures to develop a novel tracking algorithm which captures both simple shapes and also self-occluding coils, an important, yet unexplored, component of 2D worm behavior. We apply our algorithm to show that visually complex, coiled sequences are a superposition of two simpler patterns: the body wave dynamics and a head-curvature pulse. We demonstrate the precise Ω-turn dynamics of an escape response and uncover a surprising new dichotomy in spontaneous, large-amplitude coils; deep reorientations occur not only through classical Ω-shaped postures but also through larger postural excitations which we label here as δ-turns. We find that omega and delta turns occur independently, suggesting a distinct triggering mechanism, and are the serpentine analog of a random left-right step. Finally, we show that omega and delta turns occur with approximately equal rates and adapt to food-free conditions on a similar timescale, a simple strategy to avoid navigational bias., Competing Interests: The authors declare that no competing interests exist.

Cerebellar ataxias represent a spectrum of disorders which are, however, linked by common symptoms of motor incoordination and typically associated with deficiency in Purkinje cell firing activity and, often, degeneration. Cerebellar ataxias currently lack a curative agent. The endocannabinoid (eCB) system includes eCB compounds and their associated metabolic enzymes, together with cannabinoid receptors, predominantly the cannabinoid CB1 receptor (CB1 R) in the cerebellum; activation of this system in the cerebellar cortex is associated with deficits in motor coordination characteristic of ataxia, effects which can be prevented by CB1 R antagonists. Of further interest are various findings that CB1 R deficits may also induce a progressive ataxic phenotype. Together these studies suggest that motor coordination is reliant on maintaining the correct balance in eCB system signalling. Recent work also demonstrates deficient cannabinoid signalling in the mouse 'ducky(2J) ' model of ataxia. In light of these points, the potential mechanisms whereby cannabinoids may modulate the eCB system to ameliorate dysfunction associated with cerebellar ataxias are considered., (© 2016 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Regularities in animal behaviour offer insights into the underlying organizational and functional principles of nervous systems and automated tracking provides the opportunity to extract features of behaviour directly from large-scale video data. Yet how to effectively analyse such behavioural data remains an open question. Here, we explore whether a minimum description length principle can be exploited to identify meaningful behaviours and phenotypes. We apply a dictionary compression algorithm to behavioural sequences from the nematode worm Caenorhabditis elegans freely crawling on an agar plate both with and without food and during chemotaxis. We find that the motifs identified by the compression algorithm are rare but relevant for comparisons between worms in different environments, suggesting that hierarchical compression can be a useful step in behaviour analysis. We also use compressibility as a new quantitative phenotype and find that the behaviour of wild-isolated strains of C. elegans is more compressible than that of the laboratory strain N2 as well as the majority of mutant strains examined. Importantly, in distinction to more conventional phenotypes such as overall motor activity or aggregation behaviour, the increased compressibility of wild isolates is not explained by the loss of function of the gene npr-1, which suggests that erratic locomotion is a laboratory-derived trait with a novel genetic basis. Because hierarchical compression can be applied to any sequence, we anticipate that compressibility can offer insights into the organization of behaviour in other animals including humans., (© 2016 The Authors.)

To understand DNA elasticity at high forces (F>30  pN), its helical nature must be taken into account, as a coupling between twist and stretch. The prevailing model, the wormlike chain, was previously extended to include this twist-stretch coupling. Motivated by DNA's charged nature, and the known effects of ionic charges on its elasticity, we set out to systematically measure the impact of buffer ionic conditions on twist-stretch coupling. After developing a robust fitting approach, we show, using our new data set, that DNA's helical twist is stabilized at high concentrations of the magnesium divalent cation. DNA's persistence length and stretch modulus are, on the other hand, relatively insensitive to the applied range of ionic strengths.

Tremor arises from an involuntary, rhythmic muscle contraction/relaxation cycle and is a common disabling symptom of many motor-related diseases such as Parkinson disease, multiple sclerosis, Huntington disease, and forms of ataxia. In the wake of anecdotal, largely uncontrolled, observations claiming the amelioration of some symptoms among cannabis smokers, and the high density of cannabinoid receptors in the areas responsible for motor function, including basal ganglia and cerebellum, many researchers have pursued the question of whether cannabinoid-based compounds could be used therapeutically to alleviate tremor associated with central nervous system diseases. In this review, we focus on possible effects of cannabinoid-based medicines, in particular on Parkinsonian and multiple sclerosis-related tremors and the common probable molecular mechanisms. While, at present, inconclusive results have been obtained, future investigations should extend preclinical studies with different cannabinoids to controlled clinical trials to determine potential benefits in tremor.

Synaptic vesicle glycoprotein (SV)2A is a transmembrane protein found in secretory vesicles and is critical for Ca(2+) -dependent exocytosis in central neurons, although its mechanism of action remains uncertain. Previous studies have proposed, variously, a role of SV2 in the maintenance and formation of the readily releasable pool (RRP) or in the regulation of Ca(2+) responsiveness of primed vesicles. Such previous studies have typically used genetic approaches to ablate SV2 levels; here, we used a strategy involving small interference RNA (siRNA) injection to knockdown solely presynaptic SV2A levels in rat superior cervical ganglion (SCG) neuron synapses. Moreover, we investigated the effects of SV2A knockdown on voltage-dependent Ca(2+) channel (VDCC) function in SCG neurons. Thus, we extended the studies of SV2A mechanisms by investigating the effects on vesicular transmitter release and VDCC function in peripheral sympathetic neurons. We first demonstrated an siRNA-mediated SV2A knockdown. We showed that this SV2A knockdown markedly affected presynaptic function, causing an attenuated RRP size, increased paired-pulse depression and delayed RRP recovery after stimulus-dependent depletion. We further demonstrated that the SV2A-siRNA-mediated effects on vesicular release were accompanied by a reduction in VDCC current density in isolated SCG neurons. Together, our data showed that SV2A is required for correct transmitter release at sympathetic neurons. Mechanistically, we demonstrated that presynaptic SV2A: (i) acted to direct normal synaptic transmission by maintaining RRP size, (ii) had a facilitatory role in recovery from synaptic depression, and that (iii) SV2A deficits were associated with aberrant Ca(2+) current density, which may contribute to the secretory phenotype in sympathetic peripheral neurons., (© 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)