Density-dependence of functional development in spiking cortical networks grown in vitro

During development, the mammalian brain differentiates into specialized regions with distinct functional abilities. While many factors contribute to functional specialization, we explore the effect of neuronal density on the development of neuronal interactions in vitro. Two types of cortical networks, dense and sparse, with 50,000 and 12,000 total cells respectively, are studied. Activation graphs that represent pairwise neuronal interactions are constructed using a competitive first response model. These graphs reveal that, during development in vitro, dense networks form activation connections earlier than sparse networks. Link entropy analysis of dense net- work activation graphs suggests that the majority of connections between electrodes are reciprocal in nature. Information theoretic measures reveal that early functional information interactions (among 3 cells) are synergetic in both dense and sparse networks. However, during later stages of development, previously synergetic relationships become primarily redundant in dense, but not in sparse networks. Large link entropy values in the activation graph are related to the domination of redundant ensembles in late stages of development in dense networks. Results demonstrate differences between dense and sparse networks in terms of informational groups, pairwise relationships, and activation graphs. These differences suggest that variations in cell density may result in different functional specialization of nervous system tissue in vivo.Comment: 10 pages, 7 figure

Evaluation of the current knowledge limitations in breast cancer research: a gap analysis

BACKGROUND A gap analysis was conducted to determine which areas of breast cancer research, if targeted by researchers and funding bodies, could produce the greatest impact on patients. METHODS Fifty-six Breast Cancer Campaign grant holders and prominent UK breast cancer researchers participated in a gap analysis of current breast cancer research. Before, during and following the meeting, groups in seven key research areas participated in cycles of presentation, literature review and discussion. Summary papers were prepared by each group and collated into this position paper highlighting the research gaps, with recommendations for action. RESULTS Gaps were identified in all seven themes. General barriers to progress were lack of financial and practical resources, and poor collaboration between disciplines. Critical gaps in each theme included: (1) genetics (knowledge of genetic changes, their effects and interactions); (2) initiation of breast cancer (how developmental signalling pathways cause ductal elongation and branching at the cellular level and influence stem cell dynamics, and how their disruption initiates tumour formation); (3) progression of breast cancer (deciphering the intracellular and extracellular regulators of early progression, tumour growth, angiogenesis and metastasis); (4) therapies and targets (understanding who develops advanced disease); (5) disease markers (incorporating intelligent trial design into all studies to ensure new treatments are tested in patient groups stratified using biomarkers); (6) prevention (strategies to prevent oestrogen-receptor negative tumours and the long-term effects of chemoprevention for oestrogen-receptor positive tumours); (7) psychosocial aspects of cancer (the use of appropriate psychosocial interventions, and the personal impact of all stages of the disease among patients from a range of ethnic and demographic backgrounds). CONCLUSION Through recommendations to address these gaps with future research, the long-term benefits to patients will include: better estimation of risk in families with breast cancer and strategies to reduce risk; better prediction of drug response and patient prognosis; improved tailoring of treatments to patient subgroups and development of new therapeutic approaches; earlier initiation of treatment; more effective use of resources for screening populations; and an enhanced experience for people with or at risk of breast cancer and their families. The challenge to funding bodies and researchers in all disciplines is to focus on these gaps and to drive advances in knowledge into improvements in patient care

Conservation physiology of marine fishes: state of the art and prospects for policy

The state of the art of research on the environmental physiology of marine fishes is reviewed from the perspective of how it can contribute to conservation of biodiversity and fishery resources. A major constraint to application of physiological knowledge for conservation of marine fishes is the limited knowledge base; international collaboration is needed to study the environmental physiology of a wider range of species. Multifactorial field and laboratory studies on biomarkers hold promise to relate ecophysiology directly to habitat quality and population status. The 'Fry paradigm' could have broad applications for conservation physiology research if it provides a universal mechanism to link physiological function with ecological performance and population dynamics of fishes, through effects of abiotic conditions on aerobic metabolic scope. The available data indicate, however, that the paradigm is not universal, so further research is required on a wide diversity of species. Fish physiologists should interact closely with researchers developing ecological models, in order to investigate how integrating physiological information improves confidence in projecting effects of global change; for example, with mechanistic models that define habitat suitability based upon potential for aerobic scope or outputs of a dynamic energy budget. One major challenge to upscaling from physiology of individuals to the level of species and communities is incorporating intraspecific variation, which could be a crucial component of species' resilience to global change. Understanding what fishes do in the wild is also a challenge, but techniques of biotelemetry and biologging are providing novel information towards effective conservation. Overall, fish physiologists must strive to render research outputs more applicable to management and decision-making. There are various potential avenues for information flow, in the shorter term directly through biomarker studies and in the longer term by collaborating with modellers and fishery biologists.EU COST Action FA1004 Conservation Physiology of Marine Fishesinfo:eu-repo/semantics/publishedVersio

Non-invasive ventilation (NIV) as an aid to rehabilitation in acute respiratory disease

<p>Abstract</p> <p>Background</p> <p>Non-invasive ventilation (NIV) can increase exercise tolerance, reduce exercise induced desaturation and improve the outcome of pulmonary rehabilitation in patients with chronic respiratory disease. It is not known whether it can be applied to increase exercise capacity in patients admitted with non-hypercapnic acute exacerbations of COPD (AECOPD). We investigated the acceptability and feasibility of using NIV for this purpose.</p> <p>Methods</p> <p>On a single occasion, patients admitted with an acute exacerbation of chronic respiratory disease who were unable to cycle for five minutes at 20 watts attempted to cycle using NIV and their endurance time (T_lim) was recorded. To determine feasibility of this approach in clinical practice patients admitted with AECOPD were screened for participation in a trial of regular NIV assisted rehabilitation during their hospital admission.</p> <p>Results</p> <p>In 12 patients tested on a single occasion NIV increased T_limfrom 184(65) seconds to 331(229) seconds (p = 0.04) and patients desaturated less (median difference = 3.5%, p = 0.029). In the second study, 60 patients were admitted to hospital during a three month period of whom only 18(30)% were eligible to participate and of these patients, only four (7%) consented to participate.</p> <p>Conclusion</p> <p>NIV improves exercise tolerance in patients with acute exacerbations of chronic respiratory disease but the applicability of this approach in routine clinical practice may be limited.</p> <p>Trial registration</p> <p><url>http://www.controlled-trials.com/ISRCTN35692743</url></p

Abstracts from the NIHR INVOLVE Conference 2017

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Reciprocal homeostatic reactions to chronic excitatory synaptic receptor inactivation in developing cerebral cortex networks

Chronic blockade of actively excitatory glutamatergic synaptic receptors in co-cultured organotypic rodent neocortex explants leads to a compensatory up-regulation of otherwise inactive input channels so as to maintain almost normal levels of ongoing bursts of action potentials. We report here that this homeostatic return of spontaneous (now kainate receptor driven) firing is accompanied by a reciprocal down-regulation of blocked AMPA and NMDA receptors, such that the developing cortical network is protected against becoming hyperactive when those synaptic inputs are again able to transmit normally

From Neural Plate to Cortical Arousal—A Neuronal Network Theory of Sleep Derived from in Vitro “Model” Systems for Primordial Patterns of Spontaneous Bioelectric Activity in the Vertebrate Central Nervous System

In the early 1960s intrinsically generated widespread neuronal discharges were discovered to be the basis for the earliest motor behavior throughout the animal kingdom. The pattern generating system is in fact programmed into the developing nervous system, in a regionally specific manner, already at the early neural plate stage. Such rhythmically modulated phasic bursts were next discovered to be a general feature of developing neural networks and, largely on the basis of experimental interventions in cultured neural tissues, to contribute significantly to their morpho-physiological maturation. In particular, the level of spontaneous synchronized bursting is homeostatically regulated, and has the effect of constraining the development of excessive network excitability. After birth or hatching, this “slow-wave” activity pattern becomes sporadically suppressed in favor of sensory oriented “waking” behaviors better adapted to dealing with environmental contingencies. It nevertheless reappears periodically as “sleep” at several species-specific points in the diurnal/nocturnal cycle. Although this “default” behavior pattern evolves with development, its essential features are preserved throughout the life cycle, and are based upon a few simple mechanisms which can be both experimentally demonstrated and simulated by computer modeling. In contrast, a late onto- and phylogenetic aspect of sleep, viz., the intermittent “paradoxical” activation of the forebrain so as to mimic waking activity, is much less well understood as regards its contribution to brain development. Some recent findings dealing with this question by means of cholinergically induced “aroused” firing patterns in developing neocortical cell cultures, followed by quantitative electrophysiological assays of immediate and longterm sequelae, will be discussed in connection with their putative implications for sleep ontogeny