Anaesthetic modulation of ion channel kinetics in bovine chromaffin cells

The thesis describes a patch clamp study of the action of anaesthetics on the ion channels primarily responsible for initiating secretion in bovine chromaffin cells. The adrenal chromaffin cell is homologous with sympathetic post-ganglionic neurones and was chosen as a model for studying excitatory neuronal synapses. Pre- and post- synaptic events are modelled by effects on the voltage-gated calcium channels and nicotinic acetylcholine receptor channel respectively. The overall aim has been to describe anaesthetic depression of excitatory synaptic transmission at the ion channel level. Results of experiments with a representative range of anaesthetic agents are shown. Modulation of the nicotinic receptor channel has been studied at the level of whole cell currents and single ion channels. Whole cell macroscopic currents were subjected to spectral analysis to derive kinetic parameters of channel gating. These parameters were also calculated from single channel studies and the results used to derive models explaining the modulation of nicotinic acetylcholine receptor channels by anaesthetics. It is shown that while there are common features in the action of different agents, the detailed mechanism by which they inhibit nicotinic gated ion channels varies. Prior to investigating the action of anaesthetics on calcium channel currents, a study was made using a variety of voltage pulse protocols and selective channel blockers to characterise the macroscopic current and asses the contribution of the various calcium channel sub-types. It is shown that calcium currents in chromaffin cells have two components, probably carried by L and N type channels as described by other workers. Of the anaesthetics studied, all but procaine reduced whole cell calcium channel currents within a relevant concentration range. A major component of the reduction in ion flux was due to an enhanced rate at which currents decayed after being activated by depolarising voltage pulses. This was observed with all effective agents, though the magnitude of the effect varied and it was not possible to ascribe it to a selective action on either channel type

Analogues of Entropy in Bi-Free Probability Theory: Microstates

In this paper, we extend the notion of microstate free entropy to the bi-free setting. In particular, using the bi-free analogue of random matrices, microstate bi-free entropy is defined. Properties essential to an entropy theory are developed, such as the behaviour of the entropy when transformations on the left variables or on the right variables are performed. In addition, the microstate bi-free entropy is demonstrated to be additive over bi-free collections provided additional regularity assumptions are included and is computed for all bi-free central limit distributions. Moreover, an orbital version of bi-free entropy is examined which provides a tighter upper bound for the subadditivity of microstate bi-free entropy and provides an alternate characterization of bi-freeness in certain settings.Comment: (new version contains corrections, orbital bi-free entropy, and a new characterization of bi-freenness

Discours sur la démence et le déclin au Royaume-Uni

The notion of independence is prominent in current strategies to address the social exclusion of people with dementia in the United Kingdom, as part of a broader narrative of “living well” with the condition. This article explores the practical implications of applying this notion. It is based on a study of six qualitative interviews with researchers developing a psychosocial intervention in this country. An analysis of their perspectives and experiences presents how the application of this concept aims to promote agency and an active lifestyle in people experiencing cognitive decline. This intervention thus reflects a narrative of stabilization in dementia contrasting with its progressive nature. Two areas of tension emerge from this narrative in the intervention, related to 1) the normativity attached to the principle of independence, and 2) the risk of presenting dependency as a choice. In view of these tensions, this article argues that the predominance of the principle of independence risks naturalizing some of the exclusion experienced by people whose dependency prevents them from taking part in this type of intervention. This article then proposes the concept of technologies of omission as an analytical category to study societal interventions, strategies, and narratives that omit the position of people in situations of dependency, thus prompting reflection on our selective relationship to cognitive decline and aging in society

Quantitative differences in developmental profiles of spontaneous activity in cortical and hippocampal cultures.

BACKGROUND: Neural circuits can spontaneously generate complex spatiotemporal firing patterns during development. This spontaneous activity is thought to help guide development of the nervous system. In this study, we had two aims. First, to characterise the changes in spontaneous activity in cultures of developing networks of either hippocampal or cortical neurons dissociated from mouse. Second, to assess whether there are any functional differences in the patterns of activity in hippocampal and cortical networks. RESULTS: We used multielectrode arrays to record the development of spontaneous activity in cultured networks of either hippocampal or cortical neurons every 2 or 3 days for the first month after plating. Within a few days of culturing, networks exhibited spontaneous activity. This activity strengthened and then stabilised typically around 21 days in vitro. We quantified the activity patterns in hippocampal and cortical networks using 11 features. Three out of 11 features showed striking differences in activity between hippocampal and cortical networks: (1) interburst intervals are less variable in spike trains from hippocampal cultures; (2) hippocampal networks have higher correlations and (3) hippocampal networks generate more robust theta-bursting patterns. Machine-learning techniques confirmed that these differences in patterning are sufficient to classify recordings reliably at any given age as either hippocampal or cortical networks. CONCLUSIONS: Although cultured networks of hippocampal and cortical networks both generate spontaneous activity that changes over time, at any given time we can reliably detect differences in the activity patterns. We anticipate that this quantitative framework could have applications in many areas, including neurotoxicity testing and for characterising the phenotype of different mutant mice. All code and data relating to this report are freely available for others to use.PC and AM were supported by the Wellcome Trust Genes to Cognition programme. PC received additional support from the Biotechnology and Biological Sciences Research Council (BB/H008608/1). EC was supported by a Wellcome Trust PhD studentship and Cambridge Biomedical Research Centre studentship. SJE was supported by an Engineering and Physical Sciences Research Council grant (EP/E002331/1).This is the final published version. It first appeared at http://link.springer.com/article/10.1186%2Fs13064-014-0028-0

Emergence of rich-club topology and coordinated dynamics in development of hippocampal functional networks in vitro.

Recent studies demonstrated that the anatomical network of the human brain shows a "rich-club" organization. This complex topological feature implies that highly connected regions, hubs of the large-scale brain network, are more densely interconnected with each other than expected by chance. Rich-club nodes were traversed by a majority of short paths between peripheral regions, underlining their potential importance for efficient global exchange of information between functionally specialized areas of the brain. Network hubs have also been described at the microscale of brain connectivity (so-called "hub neurons"). Their role in shaping synchronous dynamics and forming microcircuit wiring during development, however, is not yet fully understood. The present study aimed to investigate the role of hubs during network development, using multi-electrode arrays and functional connectivity analysis during spontaneous multi-unit activity (MUA) of dissociated primary mouse hippocampal neurons. Over the first 4 weeks in vitro, functional connectivity significantly increased in strength, density, and size, with mature networks demonstrating a robust modular and small-world topology. As expected by a "rich-get-richer" growth rule of network evolution, MUA graphs were found to form rich-clubs at an early stage in development (14 DIV). Later on, rich-club nodes were a consistent topological feature of MUA graphs, demonstrating high nodal strength, efficiency, and centrality. Rich-club nodes were also found to be crucial for MUA dynamics. They often served as broker of spontaneous activity flow, confirming that hub nodes and rich-clubs may play an important role in coordinating functional dynamics at the microcircuit level.M.S.S. is supported by a PhD studentship funded by a Core Award from the Medical Research Council and the Wellcome Trust to the Behavioural and Clinical Neuroscience Institute (MRC Ref G1000183; WT Ref 093875/Z/10/Z) and by the Studienstiftung des deutschen Volkes. Additional support for this study from the Biotechnology and Biological Sciences Research Council (BBSRC Ref BB/H008608/1) is gratefully acknowledged.This is the final published version. It first appeared at http://www.jneurosci.org/content/35/14/5459.full