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Reproduction de : Thèse de doctorat : Neuropsychologie : Lyon 2 : 2006. / Titre provenant de l'écran-titre. Bibliogr.

Angelman syndrome (AS), a genetic disorder occurring in approximately one in every 15,000 births, is characterized by severe mental retardation, seizures, difficulty speaking and ataxia. The gene responsible for AS was discovered to be UBE3A and encodes an E6-AP ubiquitin ligase. A unique feature of this gene is that it undergoes maternal imprinting in a neuron-specific manner. In the majority of AS cases, there is a mutation or deletion in the maternally inherited UBE3A gene, although other cases are the result of uniparental disomy or mismethylation of the maternal gene. While most human disorders characterized by severe mental retardation involve abnormalities in brain structure, no gross anatomical changes are associated with AS. Although it was previously believed that UBE3A was imprinted in a brain region-specific manner, primarily in the hippocampus and cortex, recent evidence indicates that there is a widespread knockdown of Ube3a protein throughout the AS mouse brain. As a result, it became necessary to evaluate AS human brain samples to verify the relevance and accuracy of the AS mouse model. It was determined that Ube3a is deficient throughout all major brain regions in humans with AS. The remainder of this dissertation work was focused on determining if increased UBE3A expression in the AS mouse brain would be sufficient to rescue the AS phenotype. The results show that adeno-associated virus-mediated UBE3A delivery is not effective in the AS neonatal brain. In the adult AS mouse brain, however, it increased Ube3a in the hippocampus to near wild-type levels. This was sufficient to rescue the associative fear conditioning learning deficit in the AS mouse and improve learning and memory in the Morris water maze. These studies are the first to demonstrate that increased protein production in the adult AS mouse is sufficient to improve the AS phenotype, indicating that the symptoms of AS are not necessarily embryonic developmental.

<p> The ability to flexibly control or inhibit unwanted actions is critical for everyday behavior. Lack of this capacity is characteristic of numerous psychiatric diseases including attention deficit hyperactivity disorder (ADHD). My project is designed to study the neural underpinnings of response inhibition and to what extent these mechanisms are disrupted in animals with impaired impulse control. I therefore recorded single neurons from dorsal striatum, orbitofrontal cortex, and medial prefrontal cortex from rats performing a novel rodent variant of the classic "stop signal" task used in clinical settings. This task asks motivated rats to repeatedly produce simple actions to obtain rewards while needing to semi-occasionally inhibit an already initiated response. To take this a step further, I compared normal rats to rats prenatally exposed to nicotine in order to better understand the mechanism underlying inhibitory control. Rats exposed to nicotine before birth show abnormal attention, poor inhibitory control, and brain deficits consistent with impairments seen in humans prenatally exposed to nicotine and those with ADHD.</p><p> I found that dorsal striatum neurons tend to encode the direction of a response and the motor refinement necessary to guide behaviors within the task rather than playing a causal role in response inhibition. However the orbitofrontal cortex, a direct afferent of dorsal striatum, possesses the capacity to inform the striatum of the correct action during response inhibition within the critical time window required to flexibly alter an initiated movement. On the other hand, medial prefrontal cortex functions as a conflict &ldquo;monitor&rdquo; to broadly increase preparedness for flexible response inhibition by aggregating current and past conflict history. Lastly, rat pups exposed to nicotine during gestation exhibit faster movement speeds and reduced capacity for inhibitory behavior. Physiologically, prenatal nicotine exposure manifests in a hypoactive prefrontal cortex, diminished encoding of task parameters, and reduced capacity to maintain conflict information.</p>

EphB receptor tyrosine kinases regulate cell-cell contacts throughout nervous system development, mediating processes as diverse as axon guidance, topographic mapping, neuronal migration and synapse formation. EphBs bind to a group of ligands, ephrin-Bs, which span the plasma membrane, thus allowing for bidirectional signaling between cells. Since EphBs are capable of multiple modes of signaling, and since they regulate numerous interdependent stages of development, it has been challenging to define which signaling functions of EphBs mediate particular developmental events. To overcome this hurdle, we developed an approach combining chemical biology with genetic engineering to reversibly inhibit EphB receptors in vivo. By mutating a residue in the receptor’s ATP-binding pocket, we rendered its kinase activity sensitive to reversible inhibition by PP1 analogs that do not inhibit wild type receptors. We engineered triple knockin mice bearing this mutation in which the kinase activity of EphB1, EphB2, and EphB3 can be rapidly, reversibly, and specifically blocked. Since we are able to block the kinase activity of EphBs while leaving their scaffolding and reverse signaling capabilities intact, we can precisely isolate the role of the kinase domain. In addition, acute inhibition can circumvent the developmental compensation that may occur after genetic mutations and can even allow the controlled study of EphBs in the mature brain and in disease models. Using these mice, termed analog-sensitive EphB triple knockin (AS-EphB TKI) mice, we demonstrate a requirement for the kinase-dependent signaling of EphBs in the collapse of retinal ganglion cell growth cones in vitro and the guidance of retinal axons at the optic chiasm in vivo. In addition, we show that the formation of several cortical axon tracts, including the corpus callosum, requires EphB tyrosine kinase signaling. In contrast, we find that steps in synapse development that are thought to be EphB-dependent occur normally when the kinase activity of EphBs is inhibited. We conclude that a cardinal in vivo function of EphB signaling, the ability to mediate axon guidance via growth cone repulsion, requires the tyrosine kinase activity of EphBs, while the development of functional excitatory synapses is independent of EphB tyrosine kinase activity.

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In this doctoral thesis, several aspects of information integration and learning in neural systems are investigated at the levels of single neurons, networks, and perception. In the first study presented here, we asked the question of how contextual, multiplicative interactions can be mediated in single neurons by the physiological mechanisms available in the brain. Multiplicative interactions are omnipresent in the nervous system and although a wealth of possible mechanisms were proposed over the last decades, the physiological origin of multiplicative interactions in the brain remains an open question. We investigated permissive gating as a possible multiplication mechanism. We proposed an integrate-and-fire model neuron that incorporates a permissive gating mechanism and investigated the model analytically and numerically due to its abilities to realize multiplication between two input streams. The applied gating mechanism realizes multiplicative interactions of firing rates on a wide range of parameters and thus provides a feasible model for the realization of multiplicative interactions on the single neuron level. In the second study we asked the question of how gaze-invariant representations of visual space can develop in a self-organizing network that incorporates the gating model neuron presented in the first study. To achieve a stable representation of our visual environment our brain needs to transform the representation of visual stimuli from a retina-centered coordinate system to a frame of reference that is independent of changes in gaze direction. In the network presented here, receptive fields and gain fields organized in overlayed topographic maps that reflected the spatio-temporal statistics of the training input stream. Topographic maps supported a gaze-invariant representation in an output layer when the network was trained with natural input statistics. Our results show that gaze-invariant representations of visual space can be learned in an unsupervised way by a biologically plausible network based on the spatio-temporal statistics of visual stimulation and eye position signals under natural viewing conditions. In the third study we investigated psychophysically the effect of a three day meditative Zen retreat on tactile abilities of the finger tips. Here, meditators strongly altered the statistics of their attentional focus by focussing sustained attention on their right index finger for hours. Our data shows that sustained sensory focussing on a particular body part, here the right index finger, significantly affects tactile acuity indicating that merely changing the statistics of the attentional focus without external stimulation or training can improve tactile acuity. In the view of activity-dependent plasticity that is outlined in this thesis, the main driving force for development and alterations of neural representations is nothing more than neural activity itself. Patterns of neural activity shape our brains during development and significant changes in the patterns of neural activity inevitably change mature neural representations. At the same time, the patterns of neural activity are formed by environmental sensory inputs as well as by contextual, multiplicative inputs like gaze-direction or by internally generated signals like the attentional focus. In this way, our environments as well as our inner mental states shape our neural representations and our perception at any time.

Most studies, investigating human time perception, have demonstrated a difference between subjective and objective timing. Very common are, for example, results showing that visual intervals are judged shorter than physically equivalent auditory intervals. Recent studies have also found differences between motor and perceptual timing. Considering those perceived differences, the idea has been proposed that the brain might employ distributed (modality- specific) timing mechanisms rather than one amodal timing mechanism. Distributed timing mechanisms and therefore independent temporal estimates would be convenient in the computation for reliability-based multisensory or sensorimotor integration, as predicted by Bayesian inference. Several studies have shown that multisensory temporal estimates can be predicted by reliability-based integration models, as for example the Maximum Likelihood Estimation (MLE) model. Reliability-based integration studies in time research are still fairly rare and discussed controversially, and especially studies investigating sensorimotor integration are mostly missing. The aim of this cumulative thesis was to investigate sensorimotor temporal reproduction with a focus on the influence of sensory (mainly auditory) feedback on motor timing. Here fore, in all studies a sensorimotor temporal reproduction paradigm was employed, and sensory and motor estimates were treated as different/independent estimates. First, we investigated the effect of onset and offset delayed sensory feedback on temporal reproduction (Chapter 2.1). Second, perceptual and motor timing were compared explicitly and then a reliability-based model was used to predict the observed sensorimotor reproduction times (Chapter 2.2). In a third study, we manipulated the prior representation of the standard duration, using different adaptation conditions (Chapter 2.3). The findings showed that if the onset of a feedback stimulus was delayed in relation to an action (in contrast to when the feedback signal was started before the action), reproduced durations increased immediately, as soon as a delay is introduced. Offset-delayed sensory feedback, on the other hand, only induced a minor decrease in reproduction times and this effect could only be observed with auditory feedback. In comparison to auditory comparison estimates, which were shown to be fairly precise, pure motor reproduction as well as auditory reproduction was found to be consistently overestimated. The observed overestimation bias in auditory reproduction was reduced, compared to pure motor reproduction. This pattern of result could be shown for various standard durations and different signal-to-noise ratios (SNR) in the compared/reproduced tones. Further, a reliability-based model 4 predicted observed auditory reproduction biases successfully. In the third study, we could show that shifting the temporal range of accuracy feedback, manipulating the SNR of the reproduced tone, as well as introducing a manipulation of the reproduced tone onset, led to significant changes in the prior representation of the standard duration. Only manipulating the reproduced tone onset during the adaptation phase induced a reduction of auditory weights, which could be observed during the test phase. Additional trial-wise analysis confirmed that the adapted prior representation is shifted back to normal dynamically over time, once no accuracy feedback is provided anymore. The differences between observed sensory and motor estimates of time are discussed. We concluded that the finding that onset and offset delay influenced reproduction performance differentially implies that participants rather rely on the sensory feedback as a start- timing signal (at least if a causal relationship between action and sensory feedback can be established), while the motor stop is used as primary stop-timing signal. Observed sensorimotor reproduction biases and variability could be described as the weighted integration of the auditory estimate and the motor estimate. The integration reflects the brain combines multiple timing signals to improve overall performance. The prior knowledge of the standard duration in the reference memory is updated dynamically in that current sensorimotor estimates are constantly integrated with the history of duration estimates. In the end, overall implications of all the results for time perception, as well as sensory integration research are discussed. In summary, this thesis helps to improve our knowledge about sensorimotor temporal integration in a sensorimotor reproduction task on the basis of behavioral findings as well as probabilistic modeling.

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