Active dendrites enhance neuronal dynamic range

Since the first experimental evidences of active conductances in dendrites, most neurons have been shown to exhibit dendritic excitability through the expression of a variety of voltage-gated ion channels. However, despite experimental and theoretical efforts undertaken in the last decades, the role of this excitability for some kind of dendritic computation has remained elusive. Here we show that, owing to very general properties of excitable media, the average output of a model of active dendritic trees is a highly non-linear function of their afferent rate, attaining extremely large dynamic ranges (above 50 dB). Moreover, the model yields double-sigmoid response functions as experimentally observed in retinal ganglion cells. We claim that enhancement of dynamic range is the primary functional role of active dendritic conductances. We predict that neurons with larger dendritic trees should have larger dynamic range and that blocking of active conductances should lead to a decrease of dynamic range.Comment: 20 pages, 6 figure

Robustness of Learning That Is Based on Covariance-Driven Synaptic Plasticity

It is widely believed that learning is due, at least in part, to long-lasting modifications of the strengths of synapses in the brain. Theoretical studies have shown that a family of synaptic plasticity rules, in which synaptic changes are driven by covariance, is particularly useful for many forms of learning, including associative memory, gradient estimation, and operant conditioning. Covariance-based plasticity is inherently sensitive. Even a slight mistuning of the parameters of a covariance-based plasticity rule is likely to result in substantial changes in synaptic efficacies. Therefore, the biological relevance of covariance-based plasticity models is questionable. Here, we study the effects of mistuning parameters of the plasticity rule in a decision making model in which synaptic plasticity is driven by the covariance of reward and neural activity. An exact covariance plasticity rule yields Herrnstein's matching law. We show that although the effect of slight mistuning of the plasticity rule on the synaptic efficacies is large, the behavioral effect is small. Thus, matching behavior is robust to mistuning of the parameters of the covariance-based plasticity rule. Furthermore, the mistuned covariance rule results in undermatching, which is consistent with experimentally observed behavior. These results substantiate the hypothesis that approximate covariance-based synaptic plasticity underlies operant conditioning. However, we show that the mistuning of the mean subtraction makes behavior sensitive to the mistuning of the properties of the decision making network. Thus, there is a tradeoff between the robustness of matching behavior to changes in the plasticity rule and its robustness to changes in the properties of the decision making network

Dendritic Slow Dynamics Enables Localized Cortical Activity to Switch between Mobile and Immobile Modes with Noisy Background Input

Mounting lines of evidence suggest the significant computational ability of a single neuron empowered by active dendritic dynamics. This motivates us to study what functionality can be acquired by a network of such neurons. The present paper studies how such rich single-neuron dendritic dynamics affects the network dynamics, a question which has scarcely been specifically studied to date. We simulate neurons with active dendrites networked locally like cortical pyramidal neurons, and find that naturally arising localized activity – called a bump – can be in two distinct modes, mobile or immobile. The mode can be switched back and forth by transient input to the cortical network. Interestingly, this functionality arises only if each neuron is equipped with the observed slow dendritic dynamics and with in vivo-like noisy background input. If the bump activity is considered to indicate a point of attention in the sensory areas or to indicate a representation of memory in the storage areas of the cortex, this would imply that the flexible mode switching would be of great potential use for the brain as an information processing device. We derive these conclusions using a natural extension of the conventional field model, which is defined by combining two distinct fields, one representing the somatic population and the other representing the dendritic population. With this tool, we analyze the spatial distribution of the degree of after-spike adaptation and explain how we can understand the presence of the two distinct modes and switching between the modes. We also discuss the possible functional impact of this mode-switching ability

Mechanisms for the Evolution of a Derived Function in the Ancestral Glucocorticoid Receptor

Understanding the genetic, structural, and biophysical mechanisms that caused protein functions to evolve is a central goal of molecular evolutionary studies. Ancestral sequence reconstruction (ASR) offers an experimental approach to these questions. Here we use ASR to shed light on the earliest functions and evolution of the glucocorticoid receptor (GR), a steroid-activated transcription factor that plays a key role in the regulation of vertebrate physiology. Prior work showed that GR and its paralog, the mineralocorticoid receptor (MR), duplicated from a common ancestor roughly 450 million years ago; the ancestral functions were largely conserved in the MR lineage, but the functions of GRs—reduced sensitivity to all hormones and increased selectivity for glucocorticoids—are derived. Although the mechanisms for the evolution of glucocorticoid specificity have been identified, how reduced sensitivity evolved has not yet been studied. Here we report on the reconstruction of the deepest ancestor in the GR lineage (AncGR1) and demonstrate that GR's reduced sensitivity evolved before the acquisition of restricted hormone specificity, shortly after the GR–MR split. Using site-directed mutagenesis, X-ray crystallography, and computational analyses of protein stability to recapitulate and determine the effects of historical mutations, we show that AncGR1's reduced ligand sensitivity evolved primarily due to three key substitutions. Two large-effect mutations weakened hydrogen bonds and van der Waals interactions within the ancestral protein, reducing its stability. The degenerative effect of these two mutations is extremely strong, but a third permissive substitution, which has no apparent effect on function in the ancestral background and is likely to have occurred first, buffered the effects of the destabilizing mutations. Taken together, our results highlight the potentially creative role of substitutions that partially degrade protein structure and function and reinforce the importance of permissive mutations in protein evolution

MRSA in Conventional and Alternative Retail Pork Products

In order to examine the prevalence of Staphylococcus aureus on retail pork, three hundred ninety-five pork samples were collected from a total of 36 stores in Iowa, Minnesota, and New Jersey. S. aureus was isolated from 256 samples (64.8%, 95% confidence interval [CI] 59.9%–69.5%). S. aureus was isolated from 67.3% (202/300) of conventional pork samples and from 56.8% (54/95) of alternative pork samples (labeled “raised without antibiotics” or “raised without antibiotic growth promotants”). Two hundred and thirty samples (58.2%, 95% CI 53.2%–63.1%) were found to carry methicillin-sensitive S. aureus (MSSA). MSSA was isolated from 61.0% (183/300) of conventional samples and from 49.5% (47/95) of alternative samples. Twenty-six pork samples (6.6%, 95% CI 4.3%–9.5%) carried methicillin-resistant S. aureus (MRSA). No statistically significant differences were observed for the prevalence of S. aureus in general, or MSSA or MRSA specifically, when comparing pork products from conventionally raised swine and swine raised without antibiotics, a finding that contrasts with a prior study from the Netherlands examining both conventional and “biologic” meat products. In our study spa types associated with “livestock-associated” ST398 (t034, t011) were found in 26.9% of the MRSA isolates, while 46.2% were spa types t002 and t008—common human types of MRSA that also have been found in live swine. The study represents the largest sampling of raw meat products for MRSA contamination to date in the U.S. MRSA prevalence on pork products was higher than in previous U.S.-conducted studies, although similar to that in Canadian studies

Complex networks for climate model evaluation with application to statistical versus dynamical modeling of South American climate

Acknowledgments: This paper was developed within the scope of the IRTG 1740/TRP 2011/50151-0, funded by the DFG/FAPESP. Furthermore, this work has been financially supported by the Leibniz Society (project ECONS), and the Stordalen Foundation (JFD). For certain calculations, the software packages pyunicorn (Donges et al. 2013a) and igraph (Csa´rdi and Nepusz 2006) were used. The authors would like to thank Manoel F. Cardoso, Niklas Boers, and the reviewers for helpful comments on the manuscript. Open Access: This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.Peer reviewedPostprin

Parallel Computational Subunits in Dentate Granule Cells Generate Multiple Place Fields

A fundamental question in understanding neuronal computations is how dendritic events influence the output of the neuron. Different forms of integration of neighbouring and distributed synaptic inputs, isolated dendritic spikes and local regulation of synaptic efficacy suggest that individual dendritic branches may function as independent computational subunits. In the present paper, we study how these local computations influence the output of the neuron. Using a simple cascade model, we demonstrate that triggering somatic firing by a relatively small dendritic branch requires the amplification of local events by dendritic spiking and synaptic plasticity. The moderately branching dendritic tree of granule cells seems optimal for this computation since larger dendritic trees favor local plasticity by isolating dendritic compartments, while reliable detection of individual dendritic spikes in the soma requires a low branch number. Finally, we demonstrate that these parallel dendritic computations could contribute to the generation of multiple independent place fields of hippocampal granule cells

Addressing vulnerability, building resilience:community-based adaptation to vector-borne diseases in the context of global change

Abstract Background The threat of a rapidly changing planet – of coupled social, environmental and climatic change – pose new conceptual and practical challenges in responding to vector-borne diseases. These include non-linear and uncertain spatial-temporal change dynamics associated with climate, animals, land, water, food, settlement, conflict, ecology and human socio-cultural, economic and political-institutional systems. To date, research efforts have been dominated by disease modeling, which has provided limited practical advice to policymakers and practitioners in developing policies and programmes on the ground. Main body In this paper, we provide an alternative biosocial perspective grounded in social science insights, drawing upon concepts of vulnerability, resilience, participation and community-based adaptation. Our analysis was informed by a realist review (provided in the Additional file 2) focused on seven major climate-sensitive vector-borne diseases: malaria, schistosomiasis, dengue, leishmaniasis, sleeping sickness, chagas disease, and rift valley fever. Here, we situate our analysis of existing community-based interventions within the context of global change processes and the wider social science literature. We identify and discuss best practices and conceptual principles that should guide future community-based efforts to mitigate human vulnerability to vector-borne diseases. We argue that more focused attention and investments are needed in meaningful public participation, appropriate technologies, the strengthening of health systems, sustainable development, wider institutional changes and attention to the social determinants of health, including the drivers of co-infection. Conclusion In order to respond effectively to uncertain future scenarios for vector-borne disease in a changing world, more attention needs to be given to building resilient and equitable systems in the present

ICAR: endoscopic skull‐base surgery

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Predictors of positive and negative parenting behaviours: evidence from the ALSPAC cohort

Background This study aimed to establish the predictors of positive and negative parenting behaviours in a United Kingdom population. The majority of previous research has focused on specific risk factors and has used a variety of outcome measures. This study used a single assessment of parenting behaviours and started with a wide range of potential pre- and post-natal variables; such an approach might be used to identify families who might benefit from parenting interventions. Methods Using a case-control subsample of 160 subjects from the Avon Longitudinal Study of Parents and Children (ALSPAC), regression analysis was undertaken to model parenting behaviours at 12 months as measured by the Mellow Parenting Observational System. Results Positive parenting increased with maternal age at delivery, levels of education and with prenatal anxiety. More negative interactions were observed among younger mothers, mothers with male infants, with prenatal non-smokers and among mothers who perceived they had a poor support structure. Conclusions This study indicates two factors which may be important in identifying families most at risk of negative parenting: younger maternal age at delivery and lack of social support during pregnancy. Such factors could be taken into account when planning provision of services such as parenting interventions. We also established that male children were significantly more likely to be negatively parented, a novel finding which may suggest an area for future research. However the findings have to be accepted cautiously and have to be replicated, as the measures used do not have established psychometric validity and reliability data