Serial processing of kinematic signals by cerebellar circuitry during voluntary whisking

Purkinje cells (PCs) in Crus 1 represent whisker movement via linear changes in firing rate, but the circuit mechanisms underlying this coding scheme are unknown. Here we examine the role of upstream inputs to PCs—excitatory granule cells (GCs) and inhibitory molecular layer interneurons—in processing of whisking signals. Patch clamp recordings in GCs reveal that movement is accompanied by changes in mossy fibre input rate that drive membrane potential depolarisation and high-frequency bursting activity at preferred whisker angles. Although individual GCs are narrowly tuned, GC populations provide linear excitatory drive across a wide range of movement. Molecular layer interneurons exhibit bidirectional firing rate changes during whisking, similar to PCs. Together, GC populations provide downstream PCs with linear representations of volitional movement, while inhibitory networks invert these signals. The exquisite sensitivity of neurons at each processing stage enables faithful propagation of kinematic representations through the cerebellum

Composite-pulse magnetometry with a solid-state quantum sensor

The sensitivity of quantum magnetometers is challenged by control errors and, especially in the solid-state, by their short coherence times. Refocusing techniques can overcome these limitations and improve the sensitivity to periodic fields, but they come at the cost of reduced bandwidth and cannot be applied to sense static (DC) or aperiodic fields. Here we experimentally demonstrate that continuous driving of the sensor spin by a composite pulse known as rotary-echo (RE) yields a flexible magnetometry scheme, mitigating both driving power imperfections and decoherence. A suitable choice of RE parameters compensates for different scenarios of noise strength and origin. The method can be applied to nanoscale sensing in variable environments or to realize noise spectroscopy. In a room-temperature implementation based on a single electronic spin in diamond, composite-pulse magnetometry provides a tunable trade-off between sensitivities in the microT/sqrt(Hz) range, comparable to those obtained with Ramsey spectroscopy, and coherence times approaching T1

Food insecurity in adults with severe mental illness living in Northern England: A co-produced cross-sectional study

\ua9 2024 The Authors. Nutrition & Dietetics published by John Wiley & Sons Australia, Ltd on behalf of Dietitians Australia.Aim: This study aimed to explore food insecurity prevalence and experiences of adults with severe mental illness living in Northern England. Methods: This mixed-methods cross-sectional study took place between March and October 2022. Participants were adults with self-reported severe mental illness living in Northern England. The survey included demographic, health, and financial questions. Food insecurity was measured using the US Department of Agriculture Adult Food Security measure. Quantitative data were analysed using descriptive statistics and binary logistic regression; and qualitative data using content analysis. Results: In total, 135 participants completed the survey, with a mean age of 44.7 years (SD: 14.1, range: 18–75 years). Participants were predominantly male (53.3%), white (88%) and from Yorkshire (50.4%). The food insecurity prevalence was 50.4% (n = 68). There was statistical significance in food insecurity status by region (p = 0.001); impacts of severe mental illness on activities of daily living (p = 0.02); and the Covid pandemic on food access (p < 0.001). The North West had the highest prevalence of food insecurity (73.3%); followed by the Humber and North East regions (66.7%); and Yorkshire (33.8%). In multivariable binary logistic regression, severe mental illness\u27 impact on daily living was the only predictive variable for food insecurity (odds ratio = 4.618, 95% confidence interval: 1.071–19.924, p = 0.04). Conclusion: The prevalence of food insecurity in this study is higher than is reported in similar studies (41%). Mental health practitioners should routinely assess and monitor food insecurity in people living with severe mental illness. Further research should focus on food insecurity interventions in this population

Positive words carry less information than negative words

We show that the frequency of word use is not only determined by the word length \cite{Zipf1935} and the average information content \cite{Piantadosi2011}, but also by its emotional content. We have analyzed three established lexica of affective word usage in English, German, and Spanish, to verify that these lexica have a neutral, unbiased, emotional content. Taking into account the frequency of word usage, we find that words with a positive emotional content are more frequently used. This lends support to Pollyanna hypothesis \cite{Boucher1969} that there should be a positive bias in human expression. We also find that negative words contain more information than positive words, as the informativeness of a word increases uniformly with its valence decrease. Our findings support earlier conjectures about (i) the relation between word frequency and information content, and (ii) the impact of positive emotions on communication and social links.Comment: 16 pages, 3 figures, 3 table

A Dynamic Model of Interactions of Ca^(2+), Calmodulin, and Catalytic Subunits of Ca^(2+)/Calmodulin-Dependent Protein Kinase II

During the acquisition of memories, influx of Ca^(2+) into the postsynaptic spine through the pores of activated N-methyl-D-aspartate-type glutamate receptors triggers processes that change the strength of excitatory synapses. The pattern of Ca^(2+) influx during the first few seconds of activity is interpreted within the Ca^(2+)-dependent signaling network such that synaptic strength is eventually either potentiated or depressed. Many of the critical signaling enzymes that control synaptic plasticity, including Ca^(2+)/calmodulin-dependent protein kinase II (CaMKII), are regulated by calmodulin, a small protein that can bind up to 4 Ca^(2+) ions. As a first step toward clarifying how the Ca^(2+)-signaling network decides between potentiation or depression, we have created a kinetic model of the interactions of Ca^(2+), calmodulin, and CaMKII that represents our best understanding of the dynamics of these interactions under conditions that resemble those in a postsynaptic spine. We constrained parameters of the model from data in the literature, or from our own measurements, and then predicted time courses of activation and autophosphorylation of CaMKII under a variety of conditions. Simulations showed that species of calmodulin with fewer than four bound Ca^(2+) play a significant role in activation of CaMKII in the physiological regime, supporting the notion that processing ofCa^(2+) signals in a spine involves competition among target enzymes for binding to unsaturated species of CaM in an environment in which the concentration of Ca^(2+) is fluctuating rapidly. Indeed, we showed that dependence of activation on the frequency of Ca^(2+) transients arises from the kinetics of interaction of fluctuating Ca^(2+) with calmodulin/CaMKII complexes. We used parameter sensitivity analysis to identify which parameters will be most beneficial to measure more carefully to improve the accuracy of predictions. This model provides a quantitative base from which to build more complex dynamic models of postsynaptic signal transduction during learning

‘Fractional Recovery’ Analysis of a Presynaptic Synaptotagmin 1-Anchored Endocytic Protein Complex

BACKGROUND: The integral synaptic vesicle protein and putative calcium sensor, synaptotagmin 1 (STG), has also been implicated in synaptic vesicle (SV) recovery. However, proteins with which STG interacts during SV endocytosis remain poorly understood. We have isolated an STG-associated endocytic complex (SAE) from presynaptic nerve terminals and have used a novel fractional recovery (FR) assay based on electrostatic dissociation to identify SAE components and map the complex structure. The location of SAE in the presynaptic terminal was determined by high-resolution quantitative immunocytochemistry at the chick ciliary ganglion giant calyx-type synapse. METHODOLOGY/PRINCIPLE FINDINGS: The first step in FR analysis was to immunoprecipitate (IP) the complex with an antibody against one protein component (the IP-protein). The immobilized complex was then exposed to a high salt (1150 mM) stress-test that caused shedding of co-immunoprecipitated proteins (co-IP-proteins). A Fractional Recovery ratio (FR: recovery after high salt/recovery with control salt as assayed by Western blot) was calculated for each co-IP-protein. These FR values reflect complex structure since an easily dissociated protein, with a low FR value, cannot be intermediary between the IP-protein and a salt-resistant protein. The structure of the complex was mapped and a blueprint generated with a pair of FR analyses generated using two different IP-proteins. The blueprint of SAE contains an AP180/X/STG/stonin 2/intersectin/epsin core (X is unknown and epsin is hypothesized), and an AP2 adaptor, H-/L-clathrin coat and dynamin scission protein perimeter. Quantitative immunocytochemistry (ICA/ICQ method) at an isolated calyx-type presynaptic terminal indicates that this complex is associated with STG at the presynaptic transmitter release face but not with STG on intracellular synaptic vesicles. CONCLUSIONS/SIGNIFICANCE: We hypothesize that the SAE serves as a recognition site and also as a seed complex for clathrin-mediated synaptic vesicle recovery. The combination of FR analysis with quantitative immunocytochemistry provides a novel and effective strategy for the identification and characterization of biologically-relevant multi-molecular complexes

Functional Characterization of the Dendritically Localized mRNA Neuronatin in Hippocampal Neurons

Local translation of dendritic mRNAs plays an important role in neuronal development and synaptic plasticity. Although several hundred putative dendritic transcripts have been identified in the hippocampus, relatively few have been verified by in situ hybridization and thus remain uncharacterized. One such transcript encodes the protein neuronatin. Neuronatin has been shown to regulate calcium levels in non-neuronal cells such as pancreatic or embryonic stem cells, but its function in mature neurons remains unclear. Here we report that neuronatin is translated in hippocampal dendrites in response to blockade of action potentials and NMDA-receptor dependent synaptic transmission by TTX and APV. Our study also reveals that neuronatin can adjust dendritic calcium levels by regulating intracellular calcium storage. We propose that neuronatin may impact synaptic plasticity by modulating dendritic calcium levels during homeostatic plasticity, thereby potentially regulating neuronal excitability, receptor trafficking, and calcium dependent signaling

Non-Invasive In Vivo Imaging of Calcium Signaling in Mice

Rapid and transient elevations of Ca2+ within cellular microdomains play a critical role in the regulation of many signal transduction pathways. Described here is a genetic approach for non-invasive detection of localized Ca2+ concentration ([Ca2+]) rises in live animals using bioluminescence imaging (BLI). Transgenic mice conditionally expressing the Ca2+-sensitive bioluminescent reporter GFP-aequorin targeted to the mitochondrial matrix were studied in several experimental paradigms. Rapid [Ca2+] rises inside the mitochondrial matrix could be readily detected during single-twitch muscle contractions. Whole body patterns of [Ca2+] were monitored in freely moving mice and during epileptic seizures. Furthermore, variations in mitochondrial [Ca2+] correlated to behavioral components of the sleep/wake cycle were observed during prolonged whole body recordings of newborn mice. This non-invasive imaging technique opens new avenues for the analysis of Ca2+ signaling whenever whole body information in freely moving animals is desired, in particular during behavioral and developmental studies

Egr-1 Regulates Autophagy in Cigarette Smoke-Induced Chronic Obstructive Pulmonary Disease

Background: Chronic obstructive pulmonary disease (COPD) is a progressive lung disease characterized by abnormal cellular responses to cigarette smoke, resulting in tissue destruction and airflow limitation. Autophagy is a degradative process involving lysosomal turnover of cellular components, though its role in human diseases remains unclear. Methodology and Principal Findings: Increased autophagy was observed in lung tissue from COPD patients, as indicated by electron microscopic analysis, as well as by increased activation of autophagic proteins (microtubule-associated protein-1 light chain-3b, LC3B, Atg4, Atg5/12, Atg.7). Cigarette smoke extract (CSE) is an established model for studying the effects of cigarette smoke exposure in vitro. In human pulmonary epithelial cells, exposure to CSE or histone deacetylase (HDAC) inhibitor rapidly induced autophagy. CSE decreased HDAC activity, resulting in increased binding of early growth response-1 (Egr-1) and E2F factors to the autophagy gene LC3B promoter, and increased LC3B expression. Knockdown of E2F-4 or Egr-1 inhibited CSE-induced LC3B expression. Knockdown of Egr-1 also inhibited the expression of Atg4B, a critical factor for LC3B conversion. Inhibition of autophagy by LC3B-knockdown protected epithelial cells from CSE-induced apoptosis. Egr-1-1- mice, which displayed basal airspace enlargement, resisted cigarette-smoke induced autophagy, apoptosis, and emphysema. Conclusions: We demonstrate a critical role for Egr-1 in promoting autophagy and apoptosis in response to cigarette smoke exposure in vitro and in vivo. The induction of autophagy at early stages of COPD progression suggests novel therapeutic targets for the treatment of cigarette smoke induced lung injury. © 2008 Chen et al

An Inhibitory Effect of Extracellular Ca2+ on Ca2+-Dependent Exocytosis

Aim: Neurotransmitter release is elicited by an elevation of intracellular Ca 2+ concentration ([Ca 2+] i). The action potential triggers Ca 2+ influx through Ca 2+ channels which causes local changes of [Ca 2+] i for vesicle release. However, any direct role of extracellular Ca 2+ (besides Ca 2+ influx) on Ca 2+-dependent exocytosis remains elusive. Here we set out to investigate this possibility on rat dorsal root ganglion (DRG) neurons and chromaffin cells, widely used models for studying vesicle exocytosis. Results: Using photolysis of caged Ca 2+ and caffeine-induced release of stored Ca 2+, we found that extracellular Ca 2+ inhibited exocytosis following moderate [Ca 2+]i rises (2–3 mM). The IC50 for extracellular Ca 2+ inhibition of exocytosis (ECIE) was 1.38 mM and a physiological reduction (,30%) of extracellular Ca 2+ concentration ([Ca 2+]o) significantly increased the evoked exocytosis. At the single vesicle level, quantal size and release frequency were also altered by physiological [Ca 2+] o. The calcimimetics Mg 2+,Cd 2+, G418, and neomycin all inhibited exocytosis. The extracellular Ca 2+-sensing receptor (CaSR) was not involved because specific drugs and knockdown of CaSR in DRG neurons did not affect ECIE. Conclusion/Significance: As an extension of the classic Ca 2+ hypothesis of synaptic release, physiological levels of extracellular Ca 2+ play dual roles in evoked exocytosis by providing a source of Ca 2+ influx, and by directly regulatin