Simulating Cortical Feedback Modulation as Changes in Excitation and Inhibition in a Cortical Circuit Model.

Cortical feedback pathways are hypothesized to distribute context-dependent signals during flexible behavior. Recent experimental work has attempted to understand the mechanisms by which cortical feedback inputs modulate their target regions. Within the mouse whisker sensorimotor system, cortical feedback stimulation modulates spontaneous activity and sensory responsiveness, leading to enhanced sensory representations. However, the cellular mechanisms underlying these effects are currently unknown. In this study we use a simplified neural circuit model, which includes two recurrent excitatory populations and global inhibition, to simulate cortical modulation. First, we demonstrate how changes in the strengths of excitation and inhibition alter the input-output processing responses of our model. Second, we compare these responses with experimental findings from cortical feedback stimulation. Our analyses predict that enhanced inhibition underlies the changes in spontaneous and sensory evoked activity observed experimentally. More generally, these analyses provide a framework for relating cellular and synaptic properties to emergent circuit function and dynamic modulation

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Cortical Membrane Potential Signature of Optimal States for Sensory Signal Detection

SummaryThe neural correlates of optimal states for signal detection task performance are largely unknown. One hypothesis holds that optimal states exhibit tonically depolarized cortical neurons with enhanced spiking activity, such as occur during movement. We recorded membrane potentials of auditory cortical neurons in mice trained on a challenging tone-in-noise detection task while assessing arousal with simultaneous pupillometry and hippocampal recordings. Arousal measures accurately predicted multiple modes of membrane potential activity, including rhythmic slow oscillations at low arousal, stable hyperpolarization at intermediate arousal, and depolarization during phasic or tonic periods of hyper-arousal. Walking always occurred during hyper-arousal. Optimal signal detection behavior and sound-evoked responses, at both sub-threshold and spiking levels, occurred at intermediate arousal when pre-decision membrane potentials were stably hyperpolarized. These results reveal a cortical physiological signature of the classically observed inverted-U relationship between task performance and arousal and that optimal detection exhibits enhanced sensory-evoked responses and reduced background synaptic activity.Video Abstrac

Movement and Performance Explain Widespread Cortical Activity in a Visual Detection Task.

Recent studies in mice reveal widespread cortical signals during task performance; however, the various task-related and task-independent processes underlying this activity are incompletely understood. Here, we recorded wide-field neural activity, as revealed by GCaMP6s, from dorsal cortex while simultaneously monitoring orofacial movements, walking, and arousal (pupil diameter) of head-fixed mice performing a Go/NoGo visual detection task and examined the ability of task performance and spontaneous or task-related movements to predict cortical activity. A linear model was able to explain a significant fraction (33-55% of variance) of widefield dorsal cortical activity, with the largest factors being movements (facial, walk, eye), response choice (hit, miss, false alarm), and arousal and indicate that a significant fraction of trial-to-trial variability arises from both spontaneous and task-related changes in state (e.g., movements, arousal). Importantly, secondary motor cortex was highly correlated with lick rate, critical for optimal task performance (high d'), and was the first region to significantly predict the lick response on target trials. These findings suggest that secondary motor cortex is critically involved in the decision and performance of learned movements and indicate that a significant fraction of trial-to-trial variation in cortical activity results from spontaneous and task-related movements and variations in behavioral/arousal state

Genetic islands of Streptococcus agalactiae strains NEM316 and 2603VR and their presence in other Group B Streptococcal strains

BACKGROUND: Streptococcus agalactiae (Group B Streptococcus; GBS) is a major contributor to obstetric and neonatal bacterial sepsis. Serotype III strains cause the majority of late-onset sepsis and meningitis in babies, and thus appear to have an enhanced invasive capacity compared with the other serotypes that cause disease predominantly in immunocompromised pregnant women. We compared the serotype III and V whole genome sequences, strains NEM316 and 2603VR respectively, in an attempt to identify genetic attributes of strain NEM316 that might explain the propensity of strain NEM316 to cause late-onset disease in babies. Fourteen putative pathogenicity islands were described in the strain NEM316 whole genome sequence. Using PCR- and targeted microarray- strategies, the presence of these islands were assessed in a diverse strain collection including 18 colonizing isolates from healthy pregnant women, and 13 and 8 invasive isolates from infants with early- and late-onset sepsis, respectively. RESULTS: Side-by-side comparison of the strain NEM316 and strain 2603VR genomes revealed that they are extremely similar, with the only major difference being the capsulation loci and mobile genetic elements. PCR and Comparative Genome Hybridization (CGH) were used to define the presence of each island in 39 GBS isolates. Only islands I, VI, XII, and possibly X, met criteria of a true pathogenicity island, but no significant correlation was found between the presence of any of the fourteen islands and whether the strains were invasive or colonizing. Possible associations were seen between the presence of island VI and late-onset sepsis, and island X and early-onset sepsis, which warrant further investigation. CONCLUSION: The NEM316 and 2603VR strains are remarkable in that their whole genome sequences are so similar, suggesting that the capsulation loci or other genetic differences, such as pathogenicity islands, are the main determinants of the propensity of serotype III strains to cause late-onset disease. This study supports the notion that GBS strain NEM316 has four putative pathogenicity islands, but none is absolutely necessary for disease causation, whether early- or late-onset sepsis. Mobile genetic elements are a common feature of GBS isolates, with each strain having its own peculiar burden of transposons, phages, integrases and integrated plasmids. The majority of these are unlikely to influence the disease capacity of an isolate. Serotype associated disease phenotypes may thus be solely related to differences in the capsulation loci

Natural Cycles, Gases

The major gaseous components of the exhaust of stratospheric aircraft are expected to be the products of combustion (CO2 and H2O), odd nitrogen (NO, NO2 HNO3), and products indicating combustion inefficiencies (CO and total unburned hydrocarbons). The species distributions are produced by a balance of photochemical and transport processes. A necessary element in evaluating the impact of aircraft exhaust on the lower stratospheric composition is to place the aircraft emissions in perspective within the natural cycles of stratospheric species. Following are a description of mass transport in the lower stratosphere and a discussion of the natural behavior of the major gaseous components of the stratospheric aircraft exhaust

Expression of Escherichia coli F-18 Type 1 Fimbriae in the Streptomycin-Treated Mouse Large Intestine

Escherichia coli F-18, isolated from the feces of a healthy human, makes type 1 fimbriae and is an excellent colonizer of the streptomycin-treated mouse large intestine. Recently, it was shown that the inability to produce type 1 fimbriae had no effect on the ability of E. coli F-18 to colonize the streptomycin-treated mouse large intestine, suggesting the possibility that E. coli F-18 does not express type 1 fimbriae in vivo. However, we show here that E. coli F-18 does express type 1 fimbriae in mouse cecal mucus in vivo and, in fact, appears to express substantially more type 1 fimbriae in cecal mucus in vivo than in L broth in vitro

Emerging Species and Genome Editing Tools: Future Prospects in Cyanobacterial Synthetic Biology

Recent advances in synthetic biology and an emerging algal biotechnology market have spurred a prolific increase in the availability of molecular tools for cyanobacterial research. Nevertheless, work to date has focused primarily on only a small subset of model species, which arguably limits fundamental discovery and applied research towards wider commercialisation. Here, we review the requirements for uptake of new strains, including several recently characterised fast-growing species and promising non-model species. Furthermore, we discuss the potential applications of new techniques available for transformation, genetic engineering and regulation, including an up-to-date appraisal of current Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR associated protein (CRISPR/Cas) and CRISPR interference (CRISPRi) research in cyanobacteria. We also provide an overview of several exciting molecular tools that could be ported to cyanobacteria for more advanced metabolic engineering approaches (e.g., genetic circuit design). Lastly, we introduce a forthcoming mutant library for the model species Synechocystis sp. PCC 6803 that promises to provide a further powerful resource for the cyanobacterial research community

Dual gene activation and knockout screen reveals directional dependencies in genetic networks.

Understanding the direction of information flow is essential for characterizing how genetic networks affect phenotypes. However, methods to find genetic interactions largely fail to reveal directional dependencies. We combine two orthogonal Cas9 proteins from Streptococcus pyogenes and Staphylococcus aureus to carry out a dual screen in which one gene is activated while a second gene is deleted in the same cell. We analyze the quantitative effects of activation and knockout to calculate genetic interaction and directionality scores for each gene pair. Based on the results from over 100,000 perturbed gene pairs, we reconstruct a directional dependency network for human K562 leukemia cells and demonstrate how our approach allows the determination of directionality in activating genetic interactions. Our interaction network connects previously uncharacterized genes to well-studied pathways and identifies targets relevant for therapeutic intervention

Orexin-Corticotropin-Releasing Factor Receptor Heteromers in the Ventral Tegmental Area as Targets for Cocaine

Release of the neuropeptides corticotropin-releasing factor (CRF) and orexin-A in the ventral tegmental area (VTA) play an important role in stress-induced cocaine-seeking behavior. We provide evidence for pharmacologically significant interactions between CRF and orexin-A that depend on oligomerization of CRF1 receptor (CRF1R) and orexin OX1 receptors (OX1R). CRF1R–OX1R heteromers are the conduits of a negative crosstalk between orexin-A and CRF as demonstrated in transfected cells and rat VTA, in which they significantly modulate dendritic dopamine release. The cocaine target σ1 receptor (σ1R) also associates with the CRF1R–OX1R heteromer. Cocaine binding to the σ1R–CRF1R–OX1R complex promotes a long-term disruption of the orexin-A–CRF negative crosstalk. Through this mechanism, cocaine sensitizes VTA cells to the excitatory effects of both CRF and orexin-A, thus providing a mechanism by which stress induces cocaine seeking