This project applies principles from the field of Computational Neuroscience to Robotics research, in particular to develop systems inspired by how nature manages to solve sensorimotor coordination tasks. The overall aim has been to build a self-organising sensorimotor system using biologically inspired techniques based upon human cortical development which can in the future be implemented in neuromorphic hardware. This can then deliver the benefits of low power consumption and real time operation but with flexible learning onboard autonomous robots. A core principle is the Self-Organising Feature Map which is based upon the theory of how 2D maps develop in real cortex to represent complex information from the environment. A framework for developing feature maps for both motor and visual directional selectivity representing eight different directions of motion is described as well as how they can be coupled together to make a basic visuomotor system. In contrast to many previous works which use artificially generated visual inputs (for example, image sequences of oriented moving bars or mathematically generated Gaussian bars) a novel feature of the current work is that the visual input is generated by a DVS 128 silicon retina camera which is a neuromorphic device and produces spike events in a frame-free way. One of the main contributions of this work has been to develop a method of autonomous regulation of the map development process which adapts the learning dependent upon input activity. The main results show that distinct directionally selective maps for both the motor and visual modalities are produced under a range of experimental scenarios. The adaptive learning process successfully controls the rate of learning in both motor and visual map development and is used to indicate when sufficient patterns have been presented, thus avoiding the need to define in advance the quantity and range of training data. The coupling training experiments show that the visual input learns to modulate the original motor map response, creating a new visual-motor topological map.

Visual deprivation in early life causes widespread changes to the visual pathway. Structures normally dedicated to vision can be recruited for processing of the remaining senses (i.e. audition). This thesis used magnetic resonance imaging to explore how the 'visual' pathway reorganises in congenital bilateral anophthalmia, a condition where individuals are born without eyes. Anophthalmia provides a unique model of complete deprivation, since the ‘visual’ pathway has not experienced pre- or post-natal visual input. Firstly, this thesis explored reorganisation of the anophthalmic 'visual' pathway for auditory processing, from subcortical structures responding to basic sounds (Chapters 3 and 4), to higher-order occipital areas extracting meaning from speech sounds (Chapter 7). Secondly, this thesis looked to better understand the neurochemical, neuroanatomical and behavioural changes that accompany reorganisation in anophthalmia (Chapters 5 and 6). Finally, this thesis investigated whether similar changes can take place in the sighted brain after a short period of visual deprivation (Chapter 8). The experiments in this thesis provide some evidence that the lack of pre-natal visual experiences affects cross-modal reorganisation. Chapter 4 describes a unique subcortico-cortical route for auditory input in anophthalmia. Furthermore, Chapter 7 suggests that hierarchical processing of sensory information in the occipital cortex is maintained in anophthalmia, which may not be the case in congenital or early-onset blindness. However, this thesis also suggests that some reorganisation thought to be limited to anophthalmia can be found in early-onset blindness, for example with the subcortical functional changes described in Chapter 3. In addition, neurochemical, neuroanatomical and behavioural changes described in Chapters 5 and 6 are comparable to those reported in early-onset blindness, therefore demonstrating important similarities between these populations. Finally, this thesis describes how some of these functional and behavioural changes can also take place in sighted subjects after a short period of blindfolding, although this effect is extremely variable across subjects (Chapter 8). The thesis concludes by highlighting the considerable contribution of individual differences in studies of cross-modal reorganisation, and emphasises the need for larger more homogenous groups when investigating subcortical and cortical plasticity in the absence of visual input.

The sensorimotor network receives a rich variety of somesthetic afferents and outputs considerable motor efferents, both of which drive experience-dependent plasticity in the system. It remains unclear to what extent subtle changes in somaesthesis and motor function extrinsic to the brain drive plasticity in the functional organisation and anatomy of the sensorimotor network. This thesis contains a series of multimodal MRI experiments to investigate how altered-use and disuse can induce plastic changes in the sensorimotor network of the human brain. In Chapter 3, a method of mapping digit somatotopy in primary somatosensory cortex at the single-subject level using 7.0 tesla fMRI was developed and applied for a study of healthy participants. Using a phase-encoding paradigm, digit representations were accurately mapped in under 10 minutes. These maps were reproducible over time and comparable to a standard block design. In Chapter 4, a further fMRI study assessed the potential for short-term reorganisation of digit representations in primary somatosensory cortex following a manipulation whereby the right index and right middle fingers were glued together for 24 hours. There was a marked shift in the cortical overlap of adjacent digits after the glued manipulation, not seen across an equivalent control period, providing strong evidence for short-term remapping of primary somatosensory cortex. In Chapter 5, a patient study investigated plasticity associated with chronic unilateral disuse of the upper limb. A cross-sectional comparison with control participants showed reduced grey matter density in the posterior right temporoparietal junction, and increased radial diffusivity in the white matter of the right superior longitudinal fasciculus, consistent with change in the right ventral attention network. A complementary longitudinal study in Chapter 6 investigated structural plasticity associated with rehabilitation of the disused limb. There were localised increases in grey matter density, notably in the right temporoparietal junction, further implicating a potential role for regions responsible for egocentric attention in regaining upper limb use. In Chapter 7, a further patient study investigated candidate predictive biomarkers at the sub-acute stage of stroke recovery, identifying CST-lesion cross-section and sensorimotor network strength as correlates of motor function, which warrant further study. The results of the studies presented in this thesis provide a novel insight into the nature and time frame of functional and structural plasticity associated with altered use and disuse. Further study of how subtle changes in our sensory and motor use shape the sensorimotor network is warranted, particularly in the context of disuse in non-neurological clinical populations.

No description available.

Dans un premier temps, la méthode est présentée pour le cas bidimensionnel. La méthode est introduite de manière générale, en ce qui concerne les milieux discrets périodiques. L’application à la maçonnerie est ensuite abordée. La résistance homogénéisée de colonnes et murs de maçonnerie est calculée en termes de contraintes et couples-contraintes généralisées du milieu continu de Cosserat. La formulation d’une méthode basée sur le milieu de Cosserat permet la prise en compte de l’influence de la rotation relative des particules du milieu discret. Cette influence est mise en évidence à travers l’application à la maçonnerie, en comparaison avec les autres méthodes présentes dans la littérature. Dans un deuxième temps, la méthode est étendue au cas tridimensionnel. Des milieux discrets périodiques ayant leurs particules disposées le long de trois directions spatiales et montrant trois vecteurs de périodicité sont alors considérés. L’extension de la méthode s’inscrit dans le cadre de la théorie micropolaire tridimensionnelle. Cela permet la prise en compte des effets 3Dde la translation et la rotation relative des particules. L’application aux colonnes et aux murs de maçonnerie montre comment la résistance dans le plan et hors-plan de la maçonnerie sont, par ces effets, couplées. La rotation relative des blocs accentue cette interaction, qui comporte une diminution de la résistance dans-le-plan précédemment calculée. Les murs de maçonnerie sont ici décrits par des modèles de plaque micropolaire. Une formulation aux éléments finis pour des modèles de plaque micropolaire est ensuite développée. Dans un premier temps, la formulation est présentée pour l’élasticité et la dynamique. La validation d’un élément fini spécifique pour le calcul des structures est faite à l’aide d’exemples numériques. L’utilisation de cet élément sur des structures de maçonnerie est ensuite abordée, par l’implémentation d’un modèle d’homogénéisation déjà existant. Les fréquences fondamentales d’un mur maçonné sont ainsi calculées et comparées avec celle obtenues par un modèles aux éléments discrets. L’importance des rotations des blocs dans le plan du mur ainsi que leur participation dans la réponse inertielle du mur vis-à-vis des actions sismiques sont enfin investiguées. Dans un deuxième temps, la formulation aux élements finis est étendue à la plasticité, à travers l’implémentation de la théorie multi-critère pour les milieux de Cosserat. L’implémentation de cette théorie est basée sur un algorithme de projection, dont le schéma itératif de résolution est reporté. Les aspects numériques reliés à l’implémentation de l’algorithme sont examinés. Une importante limitation de l’implémentation classique de l’algoritme est montrée et une nouvelle stratégie de solution est proposée. L’élément fini de Cosserat est donc validé pour la plasticite à l’aide de nombreux exemples numériques. En conclusion, trois approches de modélisation pour les structures de maçonnerie sont proposéeset comparées. Un model continu d’homogénéisation basée sur le milieu de Cosserat est d’abord présenté. Le modèle est construit en introduisant les critères de ruptures homogénéisés calculés dans la première partie du travail dans l’élément fini développé dans la deuxième partie du travail. Un modèle continu basée sur le milieu de Cauchy est ensuite considéré. Ce denier est construit à partir de modèles déjà présents dans la littérature. L’efficacité de ces deux modèles est examinée dans la représentation du comportement élastoplastique d’un mur de maçonnerie. Leur comparaison se base sur un troisième modèle, crée à l’aide des éléments discrets. La capacité des trois modèles de modéliser l’effet d’échelle dans la formation des mécanismes de ruine est enfin investiguée sur une application pratique aux structures de maçonnerie / Developed. The method is based on the two-dimensional micropolar continuum theory and makes use of the kinematic approach of limit analysis in conjunction with a rigorous homogenization technique. The method is introduced in a general way, with regard to the genericclass of discrete periodic media made of particles of the same type. The case of masonry is presented as application. The homogenised strength domains of masonry columns and walls are retrieved in terms of the generalized stresses and couple stresses of the Cosserat continuum. The formulation of the method based on the Cosserat continuum enables the investigation of the influence of the relative rotation of the particles on the strength of the discrete medium. This influence is illustrated by the application to masonry structures, in comparison with other methods presented in the literature. The development of the homogenisation method continues with its extension to discrete periodic media made of particles disposed along three directions and showing three periodicity vectors. In this case, the approach relies on the three-dimensional micropolar theory. This enables to capture the three-dimensional effect of the relative translations and rotations of the particles constituting the discrete medium. The application to masonry columns and walls shows how the in-plane and out-of-plane actions result coupled in the assessment of masonry strength. The relative rotation of the blocks accentuates this effect, which consistently diminishes the in-plane strength. Masonry walls are finally ascribed to homogenised plates with Cosserat kinematics. A finite element formulation for Cosserat plate models is next developed. The formulation is first presented for elasticity and dynamics. The validation of a specific finite element is made by means of numerical benchmarks and patch tests. The actual use of the element is presented in an application to masonry structures. The natural frequencies of a masonry panel modelled by discrete elements are computed and compared with those given by a homogenisation model implemented in the element. This allows to investigate the role of the in-plane rotations of the blocks and to show their implication towards seismic analyses of masonry structures. The finite element formulation is next extended to the elastoplastic framework. The implementation of the multisurface plasticity theory into the Cosserat finite element is presented. The implementation of this theory is based on a projection algorithm. An important limitation of the classical implementation of this algorithm prevents its use in the framework of multisurface plasticity in efficient way. This limitation is discussed and a solution strategy is proposed. The finite element for Cosserat plate models is finally validated through numerous numerical benchmarks. In conclusion, three different modelling approaches for masonry are proposed and comviipared. A continuum model based on the Cosserat continuum is first presented. The model isconstructed by implementing the homogenised yield criteria computed based on the proposed analytical method into the developed finite element. A homogenisation model based on Cauchy continuum is next introduced. This model is constructed by selecting appropriate constitutive laws and yield criteria from the literature. The performance of those homogenisation models in representing the elastoplastic response of a masonry panel is discussed, based on the comparison with a third analogue discrete elements model. The capability of the three models in predicting the scale effect in the formation of failure mechanisms is investigated in a practical application to masonry structures

Sensory-processing sensitivity, or neurosensitivity, is a biologically-based personality dimension with implications for personality, creativity and cognition. This thesis focuses on sensitivity and its cognitive implications using recent state-of-the-art sensitivity and creativity assessments with an aim to identify objective cognitive tests of sensitivity that can supplement self-report measures, whilst providing insight into the brain basis for creativity. In Chapter 1, we review literature on creativity and sensitivity. Chapter 2 presents new evidence that positive-affect-related dimensions of sensitivity benefit creativity independently and/or interactively with Big-Five openness. Factor analysis in Chapter 3 provides important evidence that multiple dimensions of sensitivity are distinct from Big-Five personality traits. Chapter 4 and 5 explore sensitivity-related attention components in relation to endogenous and exogenous attention tasks, revealing that positive-affect-related sensitivity is characterized by differences in exogenous inhibition-of-return, and defocused, disinhibited attention states that facilitate creative potential. Chapter 6 shows sensitivity has positive implications for learning and memory processes, demonstrating that neurosensitivity affects neuroplasticity favourably. Chapter 7 explores how individual differences in unconscious cognitive mechanisms of latent inhibition (LI) may underlie higher creative potential and achievement in sensitive, open creators, as theory and evidence suggest low LI in high sensitivity and creative achievement. No evidence was found to support the hypothesis that LI differs in sensitivity, or underlies the sensitive creator. All findings are interpreted in light of a new sensitivity framework that is consistent with cognitive disinhibition and hemispheric asymmetry hypotheses of creativity and models of the creative process suggesting an important role for conscious and unconscious cognition.

Fragile X syndrome (FXS) is the most commonly inherited form of intellectual disability as well as a leading genetic cause of autism spectrum disorder. It is typically the result of a trinucleotide repeat expansion in the Fmr1 gene which leads to loss of the encoded protein, fragile X mental retardation protein (FMRP). Animal model studies over the past twenty years, mainly focusing on the Fmr1 knockout (KO) mouse, have uncovered several cellular and behavioural phenotypes associated with the loss of FMRP. Seminal work using the Fmr1 KO mouse found that metabotropic glutamate receptor mediated long-term depression (mGluR-LTD) in the hippocampus is both exaggerated (Huber et al., 2002) and independent of new protein synthesis (Nosyreva & Huber, 2006). These findings, together with studies focusing on other brain regions including the prefrontal cortex (Zhao et al., 2005) and amygdala (Suvrathan et al., 2010), have contributed to the ‘mGluR theory of FXS’ (Bear et al., 2004) which suggests that group 1 metabotropic receptor function is exaggerated in FXS. The development of genetically modified rats allows the modelling of FXS in an animal model with more complex cognitive and social behaviours than has been previously available. It also provides an opportunity for comparison of phenotypes across mammalian species that result from FMRP deletion. While the study of Fmr1 rats can significantly contribute to our understanding of FXS, we must first confirm the assumption that cellular phenotypes are conserved across mouse and rat models. In this thesis, we first aimed to test if the key cellular and synaptic phenotypes that contribute to the ‘mGluR theory of FXS’ are conserved in both the hippocampus and amygdala of Fmr1 KO rats. In agreement with mouse studies, we found mGluR-LTD was both enhanced and independent of new protein synthesis in Fmr1 KO rats. Similarly, group 1 mGluR long-term potentiation (LTP) was significantly decreased at both cortical and thalamic inputs to the lateral amygdala. Secondly, we investigated mPFC intrinsic excitability and synaptic plasticity in Fmr1 KO rats. The mPFC plays a key role in several of the cognitive functions that are affected in fragile X patients including attention, cognitive flexibility and anxiety (Goto et al., 2010). The regulation of mPFC plasticity and intrinsic excitability has also been associated with mGluR signalling. Here we found that intralaminar LTP in the mPFC showed an age-dependent deficit in Fmr1 KO rats. The mPFC also provides top down control of several cortical and subcortical regions through long-range connectivity. One pathway of interest in the study of FXS is mPFC-amygdala connectivity which is associated with fear learning and anxiety behaviours (Burgos- Robles et al., 2009). Using retrograde tracing, we showed layer 5 pyramidal neurons that provide long-range connections to the basal amygdala were intrinsically hypoexcitable in Fmr1 KO rats. This phenotype could possibly be explained through homeostatic changes in the axon initial segment which regulates neuronal excitability. This work provides the first evidence for conservation of cellular phenotypes associated with the loss of FMRP in mice and rats which will be key in the interpretation of future studies using Fmr1 KO rats. We also provide evidence of deficits in mPFC long-range connectivity to the basal amygdala, a pathway that is associated with FXS relevant behaviours. Together this highlights how study of the rat model of FXS can complement existing studies of Fmr1 KO mice as well as provide new insights into the pathophysiology resulting from the loss of FMRP. Some of this work was published in Till et al., 2015.

The cortical collecting duct of the mammalian kidney plays a critical role in the regulation of body volume, sodium pH and osmolarity and is composed of two distinct cells types, principal cells and intercalated cells. Each cell type is detectable in the kidney by the localization of specific transport proteins such as Aqp2 and ENaC in principal cells and V-ATPase B1 and Cx30 in intercalated cells. mCCDcl1 cells have been widely used as a mouse principal cell line on the basis of their physiological characteristics. In this study, the mCCDcl1 parental cell line and three sub-lines cloned from isolated single cells (Ed1, Ed2, and Ed3) were grown on filters to assess their transepithelial resistance, transepithelial voltage, equivalent short circuit current and expression of the cell-specific markers Aqp2, ENaC, V-ATPaseB1 and Cx30. The parental mCCDcl1 cell line presented amiloride-sensitive electrogenic sodium transport indicative of principal cell function, however immunocytochemistry and RT-PCR showed that some cells expressed the intercalated cell-specific markers V-ATPase B1 and Cx30, including a subset of cells also positive for Aqp2 and ENaC. The three subclonal lines contained cells that were positive for both intercalated and principal cell-specific markers. The vertical transmission of both principal and intercalated cell characteristics via single cell cloning, reveals the plasticity of mCCDcl1 cells, and a direct lineage relationship between these two physiologically important cell types, and is consistent with mCCDcl1 cells being precursor cells. For observation of live mCCDcl1 in an environment closer to in vivo conditions, a model of collecting duct was designed and developed using 3D printing of porous polymers. mCCDcl1 were cultured successfully and demonstrated improved characteristics compared to classic culture such as improved lifespan, different morphology and increased protein expression, and retained their phenotypic plasticity.

The current study was designed to analyze the roles of both α7 and α4β2 nicotinic receptors (nAChRs) in behavioral sensitization and its effects on Brain Derived Neurotrophic Factors (BDNF) and the mammalian target of rapamycin (mTOR) in the neonatal quinpirole model of schizophrenia. Animals were treated neonatally with either quinpirole (1 mg/kg) or saline starting on P1 and treatment persisted through P21. Starting on P33, animals were sensitized to nicotine (0.5 mg/kg free base) every other day up to P49. Following sensitization, brains were harvested at 1 h and 24 h post-drug treatment and BDNF protein and total mTOR activity were assessed in the nucleus accumbens. Results revealed that α7 antagonism failed to block nicotine sensitization regardless of neonatal quinpirole treatment, and appears to block the initial hypoactive response to nicotine in males but not females. In addition, α7 antagonism effectively blocked the enhanced BDNF response to nicotine in both saline and quinpirole treated animals but was ineffective at blocking mTOR at the 1 h time point, and resulted in decreases of mTOR at the 24 h time point. Antagonism of the α4β2 nAChR effectively blocked nicotine sensitization in both males and females but the higher dose resulted in a significant initial hypoactive response to nicotine. In addition, α4β2 nAChR antagonism blocked nicotine induced increases in BDNF. Total mTOR revealed that neonatal quinpirole produced a decrease in mTOR that was reversed by nicotine at the 1h but not the 24h time point and antagonism of nAChRs resulted in sex dependent effects. There results have implication towards the mechanisms underlying enhanced smoking in schizophrenia.

Alcoholism is a devastating chronic relapsing disorder with significant costs to individuals and society. The mesolimbic dopamine (DA) system plays an important role in regulating reward and addiction. GABA neurons located in the ventral tegmental area (VTA) regulate VTA DA neuron activity, and are a relevant target for alcohol in the brain. VTA GABA neurons exhibit marked hyperexcitability during withdrawal from ethanol. Past research has demonstrated that the motivational effects of opiates cause a change in VTA GABA(A) receptors in opiate-dependent animals, which switch from a GABA-induced hyperpolarization of GABA neurons to a GABA-induced depolarization. The focus of this study was to characterize excitatory and inhibitory synaptic activity in VTA GABA neurons during withdrawal from acute and chronic alcohol, and to evaluate the function of the GABA(A) receptor in the pathway to dependence. Animals were either given injections of ethanol or saline, or were kept in ethanol vapor or air chambers for three weeks. We used standard whole-cell, perforated patch, and cell-attached mode electrophysiological techniques and pharmacology to obtain recordings of cellular activity. Results for excitatory and inhibitory synaptic events were somewhat mixed and inconclusive. There is evidence for a shift in function of the GABA(A) receptor after exposure to ethanol. We found that after a single injection of ethanol (4.0 g/kg) or a chronic intermittent ethanol vapor exposure, VTA GABA neuron firing rate is less sensitive to muscimol's inhibitory effects. The neural substrates of addiction studied here are important steps in the road to alcohol dependence, and a better understanding of them may lead to novel therapies.