100 research outputs found

    Biological Protein Patterning Systems across the Domains of Life: from Experiments to Modelling

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    Distinct localisation of macromolecular structures relative to cell shape is a common feature across the domains of life. One mechanism for achieving spatiotemporal intracellular organisation is the Turing reaction-diffusion system (e.g. Min system in the bacterium Escherichia coli controlling in cell division). In this thesis, I explore potential Turing systems in archaea and eukaryotes as well as the effects of subdiffusion. Recently, a MinD homologue, MinD4, in the archaeon Haloferax volcanii was found to form a dynamic spatiotemporal pattern that is distinct from E. coli in its localisation and function. I investigate all four archaeal Min paralogue systems in H. volcanii by identifying four putative MinD activator proteins based on their genomic location and show that they alter motility but do not control MinD4 patterning. Additionally, one of these proteins shows remarkably fast dynamic motion with speeds comparable to eukaryotic molecular motors, while its function appears to be to control motility via interaction with the archaellum. In metazoa, neurons are highly specialised cells whose functions rely on the proper segregation of proteins to the axonal and somatodendritic compartments. These compartments are bounded by a structure called the axon initial segment (AIS) which is precisely positioned in the proximal axonal region during early neuronal development. How neurons control these self-organised localisations is poorly understood. Using a top-down analysis of developing neurons in vitro, I show that the AIS lies at the nodal plane of the first non-homogeneous spatial harmonic of the neuron shape while a key axonal protein, Tau, is distributed with a concentration that matches the same harmonic. These results are consistent with an underlying Turing patterning system which remains to be identified. The complex intracellular environment often gives rise to the subdiffusive dynamics of molecules that may affect patterning. To simulate the subdiffusive transport of biopolymers, I develop a stochastic simulation algorithm based on the continuous time random walk framework, which is then applied to a model of a dimeric molecular motor. This provides insight into the effects of subdiffusion on motor dynamics, where subdiffusion reduces motor speed while increasing the stall force. Overall, this thesis makes progress towards understanding intracellular patterning systems in different organisms, across the domains of life

    An information-theoretic study of neuronal spike correlations in the mammalian cerebral cortex

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    In chapter I of this thesis we present a review of the historical background of the previousspike correlation studies and current state of the problem. In the chapters II, III and IV ofthis thesis we have applied an information theoretic approach to study the role of correlationsin the neuronal code, using the responses of pairs of neurons to drifting sinusoidal gratingsof different orientations and contrasts recorded in the primary visual cortex of anesthetizedmacaque monkeys. In chapter V we investigate the effects of a focal stroke in a populationof neurons on information transmission using a computational and analytical approach tothe problem. Finally, in chapter VI we use a novel analytical approach to study effects ofhigher order correlations in a population of neurons.It has been proposed in neuroscientific literature that pooling can lead to a significant improvementin signal reliability, provided that the neurons being pooled are at most weaklycross-correlated. We have computed mutual information, and compared the informationavailable from pairs of cells with the sum of the single cell information values. This allowedus to assess the degree of synergy (or conversely, redundancy) in the coding. In chapter IIof this thesis, we show that due to a loss of information encoded in the neuronal identity ofthe cells, pooling spikes across neurons leads to a loss of a large fraction of the informationpresent in their spike trains.We have used information theory to examine whether stimulus-dependent correlation couldcontribute to the neural coding of orientation and contrast by pairs of V1 cells. To this end,in chapter III, we have used a modified version of the method of information components.This analysis revealed that although synchrony is prevalent and informative, the additionalinformation it provides is frequently offset by the redundancy arising from the similar tuningproperties of the two cells. Thus, coding is roughly independent with weak synergy orredundancy arising depending on the similarity in tuning and the temporal precision of theanalysis. Our findings suggest that this would allow cortical circuits to enjoy the stabilityprovided by having similarly tuned neurons without suffering the penalty of redundancyas the associated information transmission deficit is compensated by stimulus dependentsynchrony.In chapter IV, we present a discussion about different measures of correlations and in particularwe propose the Jensen-Shannon Divergence as a measure of the distance between thecorresponding probability distribution functions associated with each spikes fired observedpatterns. We applied this Divergence for fixed stimuli as a measure of discrimination betweencorrelated and independent firing of pairs of cells in the primary visual cortex. Thisprovides a new, information-theoretic measure of the strength of correlation. We found thatthe relative Jensen-Shannon Divergence (measured in relation to the case in which all cellsfired completely independently) decreases with respect to the difference in orientation preferencebetween the receptive field from each pair of cells. Our finding indicates that theJensen-Shannon Divergence can be used for characterizing the effective circuitry network ina population of neurons.The underlying origins of synchronized firing between cortical neurons are still under discussion.Inter-cellular communication through chemically mediated synaptic transmissionis considered a major contributor to the formation of neuronal synchrony. GABAergic inhibitoryneurons may be involved in the generation of oscillatory activity in the cortex andits synchronization. Specifically, reduction of GABAergic inhibition may favour corticalplasticity producing functional recovery following focal brain lesions. Research into neurotransmittersystems is therefore of paramount importance to understand the origins ofsynchronized spiking. However, it is necessary to understand first how simple focal abnormalitiesin GABAergic modulators can affect the information transmission in an impairedbrain tissue. In chapter V, we present a computational and analytical model of a topographicallymapped population code which includes a focal lesion as well as a process for receptivefield enlargement (plasticity). The model simulates the recovery processes in the brain, andallows us to investigate mechanisms which increase the ability of the cortex to restore lostbrain functions. We have estimated the Fisher Information carried by the topographic mapbefore and after the stroke. Our finding shows that by tuning the receptive field plasticity toa certain value, the information transfer through the cortex after stroke can be optimized.A widespread distribution of neuronal activity can generate higher-order stochastic interactions.In this case, pair-wise correlations do not uniquely determine synchronizing spiking ina population of neurons, and higher order interactions across neurons cannot be disregarded.We present a new statistical approach, using the information geometry framework, for analyzingthe probability distribution function (PDF) of spike firing patterns by consideringhigher order correlations in a neuronal pool. In chapter VI, we have studied the limit ofa large population of neurons and associated a deformation parameter to the higher ordercorrelations in the PDF. We have also performed an analytical estimation of the Fisher informationin order to evaluate the implications of higher order correlations between spikeson information transmission. This leads to a new procedure to study higher order stochasticinteractions.The overall findings of this thesis warn about making any extensive statement about therole of neuronal spike correlations without considering the general case inclusive of higherorder correlations, and suggest a need to reshape the current debate about the role of spikecorrelations across neurons.Imperial College Londo

    Treatise on Hearing: The Temporal Auditory Imaging Theory Inspired by Optics and Communication

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    A new theory of mammalian hearing is presented, which accounts for the auditory image in the midbrain (inferior colliculus) of objects in the acoustical environment of the listener. It is shown that the ear is a temporal imaging system that comprises three transformations of the envelope functions: cochlear group-delay dispersion, cochlear time lensing, and neural group-delay dispersion. These elements are analogous to the optical transformations in vision of diffraction between the object and the eye, spatial lensing by the lens, and second diffraction between the lens and the retina. Unlike the eye, it is established that the human auditory system is naturally defocused, so that coherent stimuli do not react to the defocus, whereas completely incoherent stimuli are impacted by it and may be blurred by design. It is argued that the auditory system can use this differential focusing to enhance or degrade the images of real-world acoustical objects that are partially coherent. The theory is founded on coherence and temporal imaging theories that were adopted from optics. In addition to the imaging transformations, the corresponding inverse-domain modulation transfer functions are derived and interpreted with consideration to the nonuniform neural sampling operation of the auditory nerve. These ideas are used to rigorously initiate the concepts of sharpness and blur in auditory imaging, auditory aberrations, and auditory depth of field. In parallel, ideas from communication theory are used to show that the organ of Corti functions as a multichannel phase-locked loop (PLL) that constitutes the point of entry for auditory phase locking and hence conserves the signal coherence. It provides an anchor for a dual coherent and noncoherent auditory detection in the auditory brain that culminates in auditory accommodation. Implications on hearing impairments are discussed as well.Comment: 603 pages, 131 figures, 13 tables, 1570 reference

    Metabolic and Blood Flow Properties of Functional Brain Networks Using Human Multimodal Neuroimaging

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    The brain has a high energetic cost to support neuronal activity, requiring both oxygen and glucose supply from the cerebral vascular system. Additionally, the brain functions through complex patterns of interconnectivity between neuronal assemblies giving rise to functional network architectures that can be investigated across multiple spatial scales. Different brain regions have different roles and importance within these network architectures, with some regions exhibiting more global importance by being involved in cross-network communication while other being predominantly involved in local connections. There are indications that regions exhibiting a more global role in inter networks connectivity are characterized by a higher and more efficient metabolic profile, leading to differences in metabolic properties when compared to more locally connected regions. Understanding the link between oxygen/glucose metabolism and functional features of brain network architectures, across different spatial scales, is of primary importance. This thesis consists of three original studies combining human brain resting-state multimodal neuroimaging and transcriptional data to investigate the glucose/oxygen metabolic costs of brain functional connectivity. We quantified glucose metabolism from positron emission tomography, and oxygen metabolism and functional connectivity from magnetic resonance imaging. In the first study, we highlight how the oxygen/glucose metabolism of brain regions can non-linearly relate to their functional hubness, within the resting-state networks of the brain across a nested hierarchy. We found that an increase in oxygen/glucose metabolism is associated with a non-linear increase in functional hubness where increase rates are both network- and scale-dependent. In the second study, we show specific transcriptional signatures that characterize the oxygen/glucose metabolic costs of regions involved in network global versus local centrality. This study highlights the different metabolic profiles of local and global regions, with gene expression related to oxidative metabolism and synaptic pathways being enriched in association with spatial patterns in common with resting blood flow and metabolism (oxygen and glucose) and globally-connected regions. In the third study, we demonstrate that there are oxygen/glucose metabolic costs to the functional integration and segregation of resting-state networks. We highlight that the metabolic costs of functional integration could reflect the hierarchical organization of the brain from unimodal to transmodal regions

    Whole Brain Network Dynamics of Epileptic Seizures at Single Cell Resolution

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    Epileptic seizures are characterised by abnormal brain dynamics at multiple scales, engaging single neurons, neuronal ensembles and coarse brain regions. Key to understanding the cause of such emergent population dynamics, is capturing the collective behaviour of neuronal activity at multiple brain scales. In this thesis I make use of the larval zebrafish to capture single cell neuronal activity across the whole brain during epileptic seizures. Firstly, I make use of statistical physics methods to quantify the collective behaviour of single neuron dynamics during epileptic seizures. Here, I demonstrate a population mechanism through which single neuron dynamics organise into seizures: brain dynamics deviate from a phase transition. Secondly, I make use of single neuron network models to identify the synaptic mechanisms that actually cause this shift to occur. Here, I show that the density of neuronal connections in the network is key for driving generalised seizure dynamics. Interestingly, such changes also disrupt network response properties and flexible dynamics in brain networks, thus linking microscale neuronal changes with emergent brain dysfunction during seizures. Thirdly, I make use of non-linear causal inference methods to study the nature of the underlying neuronal interactions that enable seizures to occur. Here I show that seizures are driven by high synchrony but also by highly non-linear interactions between neurons. Interestingly, these non-linear signatures are filtered out at the macroscale, and therefore may represent a neuronal signature that could be used for microscale interventional strategies. This thesis demonstrates the utility of studying multi-scale dynamics in the larval zebrafish, to link neuronal activity at the microscale with emergent properties during seizures

    Interpersonal synchrony and network dynamics in social interaction [Special issue]

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    Relationship between synaptic dysfunction and degeneration in a rodent model of dementia

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    Synaptic degeneration is currently the best biomarker correlate of cognitive decline in dementia. In the years prior to dementia onset, many neurophysiological changes are occurring hypothesised to preserve cognitive function, including alterations in synaptic and neuronal function. This thesis aims to characterise the early synaptic and neurophysiological alterations occurring in a mouse model of tauopathy-driven neurodegeneration (rTg4510). This work was performed in the somatosensory cortex, a well characterised region of the brain in the mouse, which serves as a prototypical model of the neocortex. The work presented in Chapters two and three revealed alterations in synaptic glutamatergic receptor function (reduced NMDA:AMPA receptor ratio) and intrinsic neuronal properties in prodromal tauopathy in rTg4510 mice, using in vitro whole-cell patch clamp electrophysiology. Increased dendritic branching proximal to the soma was seen in these recorded neurons following post hoc imaging of their structure. In more advanced stages of tauopathy, reductions in putative AMPA receptor-mediated spontaneous synaptic activity was observed. Significant reductions in glutamatergic receptor expression and synaptic markers was detected in both prodromal and more advanced tauopathy, quantified from isolated synaptosomes. To characterise how glutamatergic receptor dysfunction manifested in vivo, recording paradigms were optimised for in vivo two-photon targeted whole-cell patch clamp electrophysiology, outlined in Chapter four. This technique was used to simultaneously record subthreshold synaptic properties, network activity, and evoked synaptic responses in the rTg4510 model in early neurodegeneration in Chapter five. Whilst spontaneous network activity was similar between genotypes, there was an observable increase in the fast peak response of evoked activity. This work suggests that synaptic dysfunction is a feature of both prodromal and advanced tauopathy, with different functional and biochemical correlates manifesting at different stages of disease progression. Further characterisation of these processes, and how this contributes to symptomatic decline, can provide a basis to develop novel therapeutic strategies to alleviate tau-mediated synaptic and neuronal dysfunction prior to widespread cell loss

    Underlying Mechanisms of Epilepsy

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    This book is a very provocative and interesting addition to the literature on Epilepsy. It offers a lot of appealing and stimulating work to offer food of thought to the readers from different disciplines. Around 5% of the total world population have seizures but only 0.9% is diagnosed with epilepsy, so it is very important to understand the differences between seizures and epilepsy, and also to identify the factors responsible for its etiology so as to have more effective therapeutic regime. In this book we have twenty chapters ranging from causes and underlying mechanisms to the treatment and side effects of epilepsy. This book contains a variety of chapters which will stimulate the readers to think about the complex interplay of epigenetics and epilepsy

    Optoelectrical study of neuronal calcium nanodomains

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    In neurons, coupling between calcium influx and membrane voltage in pre- synaptic terminal is essential for neurotransmitter release, hyperpolarization and re- polarization and shaping of Ca2+ dendritic spikes. In the functional context, these processes are fine-tuned and controlled by complexes called “nanodomains”, which are formed by the tight association between calcium permeable channels and large conductance voltage- and calcium-gated potassium channels (BK). The structural mechanisms involved in the Ca2+ dependent activation of BK channels and deducing how these Ca2+ signals are integrated and converted into an outflux of potassium ions are intriguing questions that have to be comprehensively studied. During this PhD, we aimed to advance our knowledge about the precise func- tion of BK channels within the nanodomains as well as its structural roles in forming the complexes with N-methyl-D-aspartate glutamate receptors (NMDARs). In order to fulfil our aims, we used a combination of the most recent techniques developed in the field, including unnatural amino acids, self-labelling enzymes, superresolution microscopy and single molecule pull-down. This allowed us to study the specific structural rearrangements involved in the activation of this channel by Ca2+, as well as to develop tools to study the protein-protein interactions between BK channel and NMDARs. We demonstrated the existence of an intrasubunit bridge between the Ca2+ binding sites of BK channel as well as the crucial role of the intersubunit interfaces in the activation of the channel by this divalent cation. We reconstituted BK channel-NMDARs complexes in heterologous systems and studied the influence of GluN2 NMDAR composition in BK channel activation. Additionally, we constructed functional fusion proteins between self-labelling enzymes and BK channel, or NMDARs, and validated them under different microscopy approaches
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