Consciousness Regained: Disentangling Mechanisms, Brain Systems, and Behavioral Responses

How consciousness (experience) arises from and relates to material brain processes (the "mind-body problem") has been pondered by thinkers for centuries, and is regarded as among the deepest unsolved problems in science, with wide-ranging theoretical, clinical, and ethical implications. Until the last few decades, this was largely seen as a philosophical topic, but not widely accepted in mainstream neuroscience. Since the 1980s, however, novel methods and theoretical advances have yielded remarkable results, opening up the field for scientific and clinical progress. Since a seminal paper by Crick and Koch (1998) claimed that a science of consciousness should first search for its neural correlates (NCC), a variety of correlates have been suggested, including both content-specific NCCs, determining particular phenomenal components within an experience, and the full NCC, the neural substrates supporting entire conscious experiences. In this review, we present recent progress on theoretical, experimental, and clinical issues. Specifically, we (1) review methodological advances that are important for dissociating conscious experience from related enabling and executive functions, (2) suggest how critically reconsidering the role of the frontal cortex may further delineate NCCs, (3) advocate the need for general, objective, brain-based measures of the capacity for consciousness that are independent of sensory processing and executive functions, and (4) show how animal studies can reveal population and network phenomena of relevance for understanding mechanisms of consciousness.European Union's Horizon 2020 Research and Innovation ProgrammeHermann and Lilly Schilling FoundationGerman Research FoundationCenter for Nanoscale Microscopy and Molecular Physiology of the BrainNational Institutes of Health/National Institute of Neurological Disorders and StrokeSao Paulo Research FoundationJames S. McDonnell Foundation Scholar AwardEU Grant H2020-FETOPENCanadian Institute for Advanced ResearchAzrieli Program in Brain, Mind and ConsciousnessFLAG-ERA JTC project CANONNorwegian Research CouncilNetherlands Organization for Scientific ResearchUniv Oslo, Inst Basal Med Sci, Div Physiol, Dept Mol Med, POB 1103 Blindern, N-0317 Oslo, NorwayUniv Wisconsin, Dept Neurol, Madison, WI 53705 USAUniv Wisconsin, Dept Psychiat, Madison, WI 53719 USAUniv Fed Sao Paulo, Inst Sci & Technol, BR-12231280 Sao Jose Dos Campos, SP, BrazilUniv Milan, Dept Biomed & Clin Sci Luigi Sacco, I-20157 Milan, ItalyFdn Don Carlo Gnocchi ONLUS, Ist Ricovero & Cura Carattere Sci, I-20162 Milan, ItalyUniv Amsterdam, Swammerdam Inst Life Sci, Cognit & Syst Neurosci Grp, NL-1098 XH Amsterdam, NetherlandsUniv Amsterdam, Res Prior Program Brain & Cognit, NL-1098 XH Amsterdam, NetherlandsUniv Med Goettingen, Dept Cognit Neurol, D-37075 Gottingen, GermanyLeibniz Inst Primate Res, German Primate Ctr, D-37077 Gottingen, GermanyLeibniz Sci Campus Primate Cognit, D-37077 Gottingen, GermanyUniv Fed Sao Paulo, Inst Sci & Technol, BR-12231280 Sao Jose Dos Campos, SP, BrazilEuropean Union's Horizon 2020 Research and Innovation Programme: 720270German Research Foundation: WI 4046/1-1National Institutes of Health/National Institute of Neurological Disorders and Stroke: 1R03NS096379FAPESP: 2016/08263-9EU Grant H2020-FETOPEN: RIA 686764Web of Scienc

An integrative, multiscale view on neural theories of consciousness.

How is conscious experience related to material brain processes? A variety of theories aiming to answer this age-old question have emerged from the recent surge in consciousness research, and some are now hotly debated. Although most researchers have so far focused on the development and validation of their preferred theory in relative isolation, this article, written by a group of scientists representing different theories, takes an alternative approach. Noting that various theories often try to explain different aspects or mechanistic levels of consciousness, we argue that the theories do not necessarily contradict each other. Instead, several of them may converge on fundamental neuronal mechanisms and be partly compatible and complementary, so that multiple theories can simultaneously contribute to our understanding. Here, we consider unifying, integration-oriented approaches that have so far been largely neglected, seeking to combine valuable elements from various theories

Disulfide-Based Poly(amido amine)s for siRNA Delivery: Effects of Structure on siRNA Complexation, Cellular Uptake, Gene Silencing and Toxicity

Purpose\ud \ud RNA interference (RNAi) is a process by which small interfering RNAs (siRNA) induce sequence-specific gene silencing. Therefore, siRNA is an emerging promise as a novel therapeutic. In order to realize the high expectations for therapeutic applications, efficient delivery systems for siRNA are necessary.\ud \ud Methods\ud \ud In this study, a new series of biodegradable poly(amido amine)s with disulfide linkages in the backbone was synthesized out of N,N′-cystaminebisacrylamide (CBA), 4-amino-1-butanol (ABOL) and ethylene diamine (EDA). Effects of different percentages of butanolic side chains and protonatable fragments in the main chain on siRNA complexation, cellular uptake, gene silencing and toxicity were investigated.\ud \ud Results\ud \ud Incorporation of EDA in the polymer resulted in increased siRNA condensation. Efficient siRNA condensation was shown to be necessary for cellular uptake; however, excess of polymer decreased siRNA uptake for polymers with high amounts of EDA. Silencing efficiency did not correlate with uptake, since silencing increased with increasing w/w ratio for all polymers. More than 80% knockdown was found for polyplexes formed with polymers containing 25% or 50% EDA, which was combined with low cytotoxicity.\ud \ud Conclusions\ud \ud Poly(amido amine)s with minor fractions of protonatable fragments in the main chain are promising carriers for delivery of siRNA\u

Physicochemical and Biological Evaluation of siRNA Polyplexes Based on PEGylated Poly(amido amine)s

PURPOSE: Use of RNA interference as novel therapeutic strategy is hampered by inefficient delivery of its mediator, siRNA, to target cells. Cationic polymers have been thoroughly investigated for this purpose but often display unfavorable characteristics for systemic administration, such as interactions with serum and/or toxicity. METHODS: We report the synthesis of a new PEGylated polymer based on biodegradable poly(amido amine)s with disulfide linkages in the backbone. Various amounts of PEGylated polymers were mixed with their unPEGylated counterparts prior to polyplex formation to alter PEG content in the final complex. RESULTS: PEGylation effectively decreased polyplex surface charge, salt- or serum-induced aggregation and interaction with erythrocytes. Increasing amount of PEG in formulation also reduced its stability against heparin displacement, cellular uptake and subsequent silencing efficiency. Yet, for polyplexes with high PEG content, significant gene silencing efficacy was found, which was combined with almost no toxicity. CONCLUSIONS: PEGylated poly(amido amine)s are promising carriers for systemic siRNA delivery in vivo

Evolution of the Toarcian (Early Jurassic) carbon-cycle and global climatic controls on local sedimentary processes (Cardigan Bay Basin, UK)

The late Early Jurassic Toarcian Stage represents the warmest interval of the Jurassic Period, with an abrupt rise in global temperatures of up to ∼7 °C in mid-latitudes at the onset of the early Toarcian Oceanic Anoxic Event (T-OAE; ∼183 Ma). The T-OAE, which has been extensively studied in marine and continental successions from both hemispheres, was marked by the widespread expansion of anoxic and euxinic waters, geographically extensive deposition of organic-rich black shales, and climatic and environmental perturbations. Climatic and environmental processes following the T-OAE are, however, poorly known, largely due to a lack of study of stratigraphically well-constrained and complete sedimentary archives. Here, we present integrated geochemical and physical proxy data (high-resolution carbon-isotope data (δ13C), bulk and molecular organic geochemistry, inorganic petrology, mineral characterisation, and major- and trace-element concentrations) from the biostratigraphically complete and expanded entire Toarcian succession in the Llanbedr (Mochras Farm) Borehole, Cardigan Bay Basin, Wales, UK. With these data, we (1) construct the first high-resolution biostratigraphically calibrated chemostratigraphic reference record for nearly the complete Toarcian Stage, (2) establish palaeoceanographic and depositional conditions in the Cardigan Bay Basin, (3) show that the T-OAE in the hemipelagic Cardigan Bay Basin was marked by the occurrence of gravity-flow deposits that were likely linked to globally enhanced sediment fluxes to continental margins and deeper marine (shelf) basins, and (4) explore how early Toarcian (tenuicostatum and serpentinum zones) siderite formation in the Cardigan Bay Basin may have been linked to low global oceanic sulphate concentrations and elevated supply of iron (Fe) from the hinterland, in response to climatically induced changes in hydrological cycling, global weathering rates and large-scale sulphide and evaporite deposition

Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.

We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease

Expression and Functional Roles of Kv7/KCNQ/M-Channels in Rat Medial Entorhinal Cortex Layer II Stellate Cells

The medial entorhinal cortex (MEC) is important for spatial navigation and memory. Stellate cells (SCs) of MEC layer II provide major input to the hippocampus, and are thought to be the neuronal correlate of the grid cells. Their electrophysiological properties have been used to explain grid field formation. However, little is known about the functional roles of potassium channels in SCs. M-current is a slowly activating potassium current, active at subthreshold potentials. Although some studies have suggested that Kv7/M-channels may affect subthreshold resonance in SCs, others have found no Kv7/M-current in these cells, so the expression and roles of Kv7/M-channels in SCs are still debated. Using whole-cell voltage-clamp, we have identified a typical M-current with pharmacological properties characteristic of Kv7/M-channels in rat MEC SCs. Current-clamp experiments showed that the specific Kv7/M-channel blocker XE991 increased SCs excitability, and reduced spike frequency adaptation. Our results demonstrate that Kv7/M-channels are expressed in SCs and contribute substantially to regulation of excitability in these cells

LFP predictions from linear filters and multiple regression.

<p>(<b>A</b>) Prediction of LFP (blue) and spikes (black) using order-2 Butterworth filters at 600 Hz. The original broad-band signal is shown in red. The distortion of the spike waveform can be seen in the expanded traces in B. (<b>B</b>) Example of an extracellular spike in the original signal (red) and the corresponding high-pass (black) and low-pass (blue) filtered traces using an order-2 Butterworth filter. (<b>C</b>) Prediction of LFP and spikes using linear regression, with a sliding time-window of 100 ms. There is higher noise in the LFP estimate (blue in B) and the spike estimate (black in B) than in the original broad-band signal (red in A) and the filtered spike trace (black in A). (<b>D</b>) The same spike with original broad-band signal (red) residual from multiple regression (black) and LFP prediction from multiple regression (blue).</p