The human motor system exhibits remarkable adaptability, enabling us to maintain high levels of performance despite ever-changing requirements. There are many potential sources of error duringmovement to which the motor system may need to adapt: the properties of our bodies or tools may vary over time, either at a dynamic or a kinematic level; our senses may become miscalibrated over time and mislead us as to the state of our bodies or the true location of an intended goal; the relationship between sensory stimuli and movement goals may change. Despite these many varied ways in which our movements may be disturbed, existing models of human motor adaptation have tended to assume just a single adaptive component. In this thesis, I argue that the motor system maintains multiple components of adaptation, corresponding to the multiple potential sources of error to which we are exposed. I outline some of the shortcomings of existing adaptation models in scenarious where multiple kinds of disturbances may be present - in particular examining how different distal learning problems associated with different classes of disturbance can affect adaptation within alternative cerebellar-based learning architectures - and outline the computational challenges associated with extending these existing models. Focusing on the specific problem in which the potential disturbances are miscalibrations of vision and proprioception and changes in arm dynamics during reaching, a unified model of sensory and motor adaptation is derived based on the principle of Bayesian estimation of the disturbances given noisy observations. This model is able to account parsimoniously for previously reported patterns of sensory and motor adaptation during exposure to shifted visual feedback. However the model additionally makes the novel and surprising prediction that adaptation to a force field will also result in sensory adaptation. These predictions are confirmed experimentally. The success of the model strongly supports the idea that the motor system maintains multiple components of adaptation, which it updates according to the principles of Bayesian estimation.

Yes / In conflict with historically dominant models of time perception, recent evidence suggests that the encoding of our environment’s temporal properties may not require a separate class of neurons whose raison d'être is the dedicated processing of temporal information. If true, it follows that temporal processing should be imbued with the known selectivity found within non-temporal neurons. In the current study, we tested this hypothesis for the processing of a poorly understood stimulus parameter: visual event duration. We used sensory adaptation techniques to generate duration aftereffects: bidirectional distortions of perceived duration. Presenting adapting and test durations to the same vs different eyes utilises the visual system’s anatomical progression from monocular, pre-cortical neurons to their binocular, cortical counterparts. Duration aftereffects exhibited robust inter-ocular transfer alongside a small but significant contribution from monocular mechanisms. We then used novel stimuli which provided duration information that was invisible to monocular neurons. These stimuli generated robust duration aftereffects which showed partial selectivity for adapt-test changes in retinal disparity. Our findings reveal distinct duration encoding mechanisms at monocular, depth-selective and depthinvariant stages of the visual hierarchy. / The Wellcome Trust [WT097387].

It is well established that, following adaptation, cells adjust their sensitivity to reflect the global stimulus conditions. Two recent studies in guinea pig inferior colliculus (IC, Dean, Harper & McAlpine 2005) and rat barrel cortex (Garcia-Lazaro, Ho, Nair & Schnupp 2007) found that neural stimulus-response functions were displaced laterally in a manner that was dependent on the mean adapting stimulus. However, the direction of gain change, following adaptation to variance, was in contradiction to Information Theory, which predicts a decrease in gain with increased stimulus variance. On further analysis of the experimental data, presented within this thesis, it was revealed that the adaptive gain changes to global stimulus variance were, in fact, in the direction predicted by Information Theory. However, following adaptation to global mean amplitude, neural threshold was displaced to centre the SRF on inputs that were located on the edge of the stimulus distribution. It was found that adaptation scaled neural output such that the relationship between firing rate and local, as opposed to global, differences in stimulus amplitude was maintained; with the majority of cells responding to large differences in stimulus amplitude, on the 40ms scale. A small majority of cells responded to step-size differences, in amplitude, of either direction and were classed as novelty preferring. Adaptation to global mean was replicated in model neuron with spike-rate adaptation and tonic inhibition, which increased with stimulus mean. Adaptation to stimulus variance was replicated in three models 1: By increasing, in proportion to stimulus variance, background, excitatory and inhibitory firing rates in a balanced manner (Chance, Abbott & Reyes 2002), 2: A model of asymmetric synaptic depression (Chelaru & Dragoi 2008) and 3: a model combining non-linear input with synaptic depression. The results presented, within this thesis, demonstrate that neurons change their coding strategies depending upon the global levels of mean and variance within the sensory input. Under low noise conditions, neurons act as deviation detectors, i.e. are primed to respond to large changes in the stimulus on the tens of millisecond; however, under conditions of increased noise switch their encoding strategy in order to compute the full range of the stimulus distribution through adjusting neural gain.

Rett syndrome (RTT), a severe neurodevelopmental disorder, affects females resulting from loss-of-function mutations in the X-linked transcription factor methyl-CpG-binding protein 2 (MECP2). RTT patients show severe verbal, motor, respiratory, and intellectual impairments. We studied two forms of activity-dependent plasticity in Mecp2 mutant mice to better understand the loss of MECP2 function in neuronal circuit and sensory processing. Sensory deprivation was applied by trimming one whisker to 3 mm to study long-term cortical plasticity in Mecp2-/y mice. Intrinsic optical signaling (IOS) imaging showed the neuronal response to wiggling a non-trimmed was consistent from day 0 to 14 but reduced for the trimmed whisker by 49.0 ± 4.3% in wild type (WT) and 22.7 ± 4.6% (p=0.0135) in RTT mice. Primary hindlimb (HL) somatosensory cortical responses to vibratory stimulation were assessed by IOS and intracortical local field potential (LFP). Responses were assessed before, during and, after 1 hour of repeated HL vibratory stimulation (100Hz,1sec, ISI 6 sec) in symptomatic male (4-6 week), female (10-12 month) and pre-symptomatic young female (4 week) RTT model mice. After 1-hour, cortical responses to test vibrations were reduced by approximately 40% in RTT and WT mice as assessed by both methods. Recovery of the IOS responses (1 sec vibration at 100Hz) and LFP (300µm below pia, 7 stimuli, 100mse ISI) were tested at 15 min intervals for 1 hour after ceasing the repeated stimulation. Reduced responses persisted for at least 60 min in WT but recovered to 90-100% of normal within 15-30 min in RTT. Analysis of the LFP responses within the test train indicated that the reduced cortical sensitivity during and after continuous stimulation resulted primarily from an increase in adaptation during the 7-stimulus test train rather than a reduction in the response to a single vibratory stimulus in all groups. Retention of this increased STA is the primary cause of the persistently reduced tactile response in young WT female mice, while in RTT mice the rapid recovery of tactile sensitivity was due to the return of STA to lower, baseline levels. Male RTT mice exhibited a marked increased excitability to the first stimulus in the test train resulting in hypersensitivity to a single vibration by 45 minutes. Old females exhibited the same pattern of adaptation and recovery but retention of adaptation was less pronounced in both WT and RTT compared to younger animals suggesting an age-dependent reduction in neural plasticity may mask deficits specific to RTT. Recording sciatic nerve sensory afferent activity did not reveal any STA, persistent adaptation or sensitization of peripheral afferent endings in any groups. I propose persistent sensory adaptation mediated by increased short-term adaptation may reflect enhanced feedback by inhibitory elements of circuits within the sensory pathway. The rapid recovery of responsiveness in young female RTT mice may therefore reflect a deficit in the capacity for activity dependent plasticity to consolidate and thus could provide a platform to understand the causes of learning and cognitive deficits in RTT patients. / Graduate

Yes / Accurate time perception is critical for a number of human behaviours, such as understanding speech and the appreciation of music. However, it remains unresolved whether sensory time perception is mediated by a central timing component regulating all senses, or by a set of distributed mechanisms, each dedicated to a single sensory modality and operating in a largely independent manner. To address this issue, we conducted a range of unimodal and cross-modal rate adaptation experiments, in order to establish the degree of specificity of classical after-effects of sensory adaptation. Adapting to a fast rate of sensory stimulation typically makes a moderate rate appear slower (repulsive after-effect), and vice versa. A central timing hypothesis predicts general transfer of adaptation effects across modalities, whilst distributed mechanisms predict a high degree of sensory selectivity. Rate perception was quantified by a method of temporal reproduction across all combinations of visual, auditory and tactile senses. Robust repulsive after-effects were observed in all unimodal rate conditions, but were not observed for any cross-modal pairings. Our results show that sensory timing abilities are adaptable but, crucially, that this change is modality-specific - an outcome that is consistent with a distributed sensory timing hypothesis.

No description available.

No-vision walking is supported in the central nervous system (CNS) by a spatial updating process. This process involves the iterative updating of a mental representation of the environment using estimates of distance traveled gleaned from locomotive kinematic activity. An effective means of examining the online regulation of this process is a continuous pointing task, which requires performers to walk along a straight-line forward trajectory while keeping their right arm straight and index finger fixated on a stationary ground-level target beside the walking path. In the current thesis, no-vision continuous pointing was examined in typically calibrated and recalibrated perceptual-motor states. Shoulder and trunk joint angles provided the basis for perceptual measures that reflected spatial updating performance and kinematic measures that reflected its underlying CNS online regulation. In the typically calibrated conditions, no-vision walking demonstrated a slight perceptual underestimation of distance traveled (Study 1). In the recalibrated conditions, no-vision walking demonstrated: a) perceptual underestimation and overestimation following adaptation periods involving walking with low and high visual gains, respectively (Study 2); and b) partial recalibration following exposures to vision and arm gains (Study 3). The latter was suggested as being impacted by task specific changes in CNS multisensory integration resulting from the development of a robust task prior and/or the altering of sensory cue weights. Importantly, this thesis used a novel trajectory parsing procedure to quantify discrete CNS perceptual updating units in the shoulder plane of elevation trajectory. The starts and ends of these updating units were consistently timed to the late left-to-early right foot swing phase of the step-cycle, regardless of perceptual-motor state. This was suggested to reflect perceptual units that were purposely timed, but indirectly mapped, to this kinematic event. The perceptual differences in Studies 1 and 2 were at least partially reflected in these units. / Thesis / Doctor of Philosophy (PhD) / It is well understood that humans can effectively walk without vision to environmental locations up to 15 metres away. However, less is known about how these walking movements are controlled during the course of forward progression. This thesis fills this knowledge gap using a task that requires participants to walk forward along a straight path while keeping their right index finger pointed toward a ground-level target beside the walking path. The patterns of arm movements performed during this task are indicative of the control strategies used by the performer to mentally update their positions in space. One of the key contributions of this work is showing that humans perform this mental updating in a repetitive manner, and that these repetitions are consistently linked to early forward movements of the right leg. This pattern is maintained when walking without vision is performed in a variety of different contexts.

Sinorhizobium meliloti is a nitrogen-fixing endosymbiont of the legume Medicago sativa commonly known as alfalfa. It uses flagellar rotation and chemotaxis to seek roots of host plants to inhabit. This symbiosis serves as a great model system for studying biological nitrogen fixation and plant-microbe interactions. Since alfalfa brings enormous economic value to the USA, investments into the knowledge of the chemotaxis process that initiates symbiosis have the ability to mitigate deterioration of the environment and significantly increase food supply. The chemotaxis system in the enteric bacteria Escherichia coli is well studied and has been a great resource to understanding the process in other bacterial systems including our model organism S. meliloti. This dissertation compares and contrasts the chemotaxis features in E. coli and S. meliloti and investigates their molecular functions. Based on the understanding gained so far, we attempt to offer plausible explanations for the underlying mechanisms of the S. meliloti chemotaxis pathway. Chapter 1 describes why biological nitrogen fixation is important for agriculture and the health of our environment. This chapter also sheds light on the symbiotic relationship between alfalfa and S. meliloti, which culminates in the formation of nitrogen fixing nodules. We expound on the chemotaxis systems in E. coli and other bacteria including S. meliloti and Bacillus subtilis. In chapter 2, we compare the distribution of C-terminal pentapeptide-bearing receptors and the adaptation proteins that they tether in E. coli and S. meliloti. The stoichiometry data show that the ratio of pentapeptide-bearing chemoreceptors to chemotaxis protein (Che)R and CheB molecules are approximately 500- and 160-fold higher in S. meliloti than in E. coli, respectively. Since not all chemoreceptors in chemotactic bacteria have and utilize the pentapeptide moiety, we investigated the S. meliloti system and observed a strong interaction between CheR, activated CheB and the isolated pentapeptides via in-vitro binding studies. On the contrary, unmodified CheB showed weak binding to the pentapeptide. Through in-vivo studies, we highlighted the physiological necessity of the pentapeptide for chemotaxis. S. meliloti strains with substitutions of the conserved tryptophan residue to alanine in one or all four pentapeptide-bearing Methyl-accepting Chemotaxis Proteins (MCPs) resulted in diminished or loss of chemotaxis to glycine betaine, lysine, and acetate, ligands sensed by pentapeptide-bearing McpX and pentapeptide-lacking McpU and McpV, respectively. The flexible linker connecting the pentapeptide to the MCPs together with the pentapeptide itself were shown to be functional on pentapeptide-lacking chemoreceptors and provided adaptational assistance to other chemoreceptors that lacked a functional pentapeptide. Based on these results, we concluded that S. meliloti employs a pentapeptide-dependent adaptation system with MCPs possessing a consensus pentapeptide motif (N/D)WE(E/N)F). Finally, we postulated that the higher abundance of CheR and CheB in S. meliloti compared to E. coli compensates for the lower number of pentapeptide-bearing chemoreceptors in the chemosensory array. In chapter 3, we explored the putative phosphatase function of a novel protein, CheT, on phosphorylated S. meliloti response regulators. The kinase CheA phosphorylates both the sink response regulator, CheY1, and the flagellar motor interacting response regulator, CheY2. CheY1 competes with CheY2 for these phosphate groups, but we have discovered another layer of complexity to the story. Sequence comparison of S. meliloti CheT and the E. coli phosphatase CheZ shows little sequence homology. However, both proteins share a DXXXQ phosphatase motif. Phosphorylation assays performed using radiolabeled [γ-32P]-ATP revealed that CheT acts as a phosphatase of CheY1~P and accelerates dephosphorylation of CheY1~P by at least two-fold. Interestingly, we also discovered that CheT interacts with CheR, but this interaction did not affect the enzymatic activity of either protein under the examined conditions. Unexpectedly, a cheT deletion strain and strains carrying mutations in the phosphatase motif exhibit an increased swimming speed, a phenotype that does not conform with the model that the absence of CheT or its activity results in increased CheY2~P levels and reduced swimming speed. We concluded that a revised S. meliloti signal termination pathway should include CheT enhancing dephosphorylation of CheY1~P and sensory adaptation involving the yet unknown function of CheT on CheR. While the adaptation system in S. meliloti is unexplored, this work provides first insights into fascinating deviations and similarities to the known paradigm. We have also delivered evidence that the S. meliloti signal termination system requires a dedicated phosphatase. The knowledge gained here takes us a step closer to enhance the S. meliloti chemotaxis pathway towards improved symbiosis with alfalfa and to reduce our dependence on environmentally deleterious synthetic fertilizers. / Doctor of Philosophy / Like all living things, bacteria inhabit a constantly changing environment, hence the need to take up and process this information. Bacterial cells have evolved sophisticated biological tools to tackle this challenge of detecting, responding and adapting to environmental signals like nutrients, toxins, temperature changes, light, metabolites, etc. Motile bacteria such as Escherichia coli, a gut resident microbe, and Sinorhizobium meliloti, a soil dwelling bacterium, direct their swimming behavior in response to chemical gradients within the milieu through a process termed chemotaxis. Generally, this vital process enables a bacterium to escape harmful chemicals and gravitate towards beneficial ones. However, S. meliloti specifically employs chemotaxis to locate the roots of its plant host (alfalfa) and to establish a symbiotic relationship through which the bacteria provide essential nitrogen for plant growth in exchange for nourishment. The biological tools employed by S. meliloti for chemotaxis include environmental sensing receptors called Methyl-accepting Chemotaxis Proteins (MCPs) and proteins inside the bacterial cell that transfer information from the sensors to long, helical rotating propeller structures, called flagella. Importantly, the efficiency of this process hinges on a timely termination of information flow and the ability to adapt to prevailing stimuli while maintaining sensitivity to increasing concentration gradients. This work investigates the function of the C-terminal five amino acid motif of MCPs known to be critical for adaptation in E. coli and the phosphatase activity of a novel protein, CheT, in signal termination of S. meliloti chemotaxis system.

The aim of the diploma thesis is to evaluate the influence of the sensory adaptation on postural balance of persons between 10 - 20 years old. The measurement of postural balance on stabilometric desc without visual control in postural situations in different difficulty with and without light touch. For this study 10 blind probands and 10 probands without visual impairment are tested. We expect that blind ones will show better results in all of tested COP parameters in all postural situations than control group because of sensory adaptation. Keywords postural stability, static balance, visual impairment, blindness, sensory adaptation

Neuronale Adaptation dient dazu, eine Sinnesbahn kurzfristig an die aktuelle Umgebung des Tieres anzupassen. Ihr zeitlicher Verlauf lässt sich in der Antwort einzelner Nervenzellen direkt beobachten. Der Adaptation unterliegen eine Vielzahl verschiedener Mechanismen, die über die gesamte Sinnesbahn verteilt sein können. In der vorliegenden Arbeit wurde der Versuch unternommen, diese unterschiedlichen Betrachtungsebenen zusammenzuführen. Dazu wurden mehrere experimentelle und theoretische Studien durchgeführt. In zwei der vorgestellten Studien wurden Kombinationen aus Strominjektionen und akustischen Reizen verwendet, um intrinsische Adaptation von Netzwerkeffekten zu trennen. Dabei ergab sich in einer experimentellen Studie am auditorischen System der Heuschrecke, dass die Adaptationsmechanismen, die in verschiedenen Teilen der Hörbahn rekrutiert werden, sehr stark von Identität und Funktion der jeweils untersuchten Nervenzelle abhängen. Ähnliche Methoden ermöglichten es, im auditorischen System der Grille präsynaptische Hemmung als Substrat für die wichtige mathematische Operation der Division zu identifizieren. Zusätzlich wurden Modellierungen durchgeführt, bei denen die Frage bearbeitet wurde, wo Adaptation in der Hörbahn wirken sollte, bezogen auf zwei verschieden Aufgaben: die Lokalisation eines Signals und die neuronale Abbildung dessen zeitlicher Struktur. Die Ergebnisse dieser Studie deuten darauf hin, dass die Anforderungen für diese beiden Aufgaben sehr unterschiedliche sind. In einer vierten Studie wurde untersucht, ob die Adaptation in einem auditorischen Interneuron der Grille dazu dient, die gesamte sensorische Umgebung gut abzubilden, oder ob durch die Adaptation eine Abtrennung des jeweils lautesten Signals erreicht werden kann. Zusammenfassend lässt sich sagen, dass sowohl die Adaptationsmechanismen, als auch deren genaue Platzierung innerhalb der sensorischen Bahn wesentlich für Sinnesleistungen sind. / Neural adaptation serves to adjust the sensory pathway to the current environment of an animal. While the effect and time course of adaptation can be observed directly within single cells, its underlying cause is a combination of many different mechanisms spread out along the sensory pathway. The present work has the objective to unite these different levels of understanding of the term adaptation. In order to do so, several experimental and theoretical studies were carried out. In two of these studies, a combination of current injection and auditory stimulation was used, in order to disentangle intrinsic adaptation from network effects. In one of the studies, carried out in the auditory system of locusts, it was revealed that the mechanisms behind adaptation that are activated within different parts of the auditory system depend critically on identity and function of the cell under study. Similar methods enabled the identification of presynaptic inhibition as a possible mechanisms behind the important mathematical operation of division in the auditory system of crickets. Additionally, a modeling study pursued the question, where adaption should work in the auditory system from the perspective of two different tasks of sensory processing: identification of a signal and localization of its source. The results obtained from the model suggest conflicting demands for these two tasks and also present a solution of this conflict. In a fourth study, it was asked wether adaptation in the auditory system of crickets serves to guarantee optimal representation of the entire sensory environment or if it helps to separate one most important signal from the background. In summary, not only which mechanisms of adaptation are at work is of crucial importance for sensory processing, but also the exact placement of these along the pathway.