Graduate School of Systemic Neurosciences - Digitale Hochschulschriften der LMU

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.

Wed, 21 Aug 2013 12:00:00 +0100 http://edoc.ub.uni-muenchen.de/16122/ http://edoc.ub.uni-muenchen.de/16122/1/Krueger_Melanie.pdf Krüger, Melanie Graduate School of Systemic Neurosciences (G

Most of the commonly used antidepressants block monoamine reuptake transporters to enhance serotonergic or noradrenergic neurotransmission. Effects besides or downstream of increased monoaminergic neurotransmission are poorly understood and yet presumably important for the drugs’ mode of action. In my PhD thesis I employed proteomics and metabolomics technologies combined with in silico analyses and identified cellular pathways affected by antidepressant drug treatment. DBA/2 mice were treated with paroxetine as a representative Selective Serotonin Reuptake Inhibitor (SSRI). Hippocampal protein levels were compared between chronic paroxetine- and vehicle-treated animals using in vivo 15N metabolic labeling combined with mass spectrometry. I also studied chronic changes in the hippocampus using unbiased metabolite profiling and the time course of metabolic changes with the help of a targeted polar metabolomics profiling platform. I identified profound alterations related to hippocampal energy metabolism. Glycolytic metabolite levels acutely increased while Krebs cycle metabolite levels decreased upon chronic treatment. Changes in energy metabolism were influenced by altered glycogen metabolism rather than by altered glycolytic or Krebs cycle enzyme levels. Increased energy levels were reflected by an increased ATP/ADP ratio and by increased ratios of high-to-low energy purines and pyrimidines. Paralleling the shift towards aerobic glycolysis upon paroxetine treatment I identified decreased levels of Krebs cycle and oxidative phosphorylation enzyme levels upon the antidepressant-like 15N isotope effect in high-anxiety behavior mice. In the course of my analyses I also identified GABA, galactose-6-phosphate and leucine as biomarker candidates for the assessment of chronic paroxetine treatment effects in the periphery and myo-inositol as biomarker candidate for an early assessment of chronic treatment effects. The identified antidepressant drug treatment affected molecular pathways and novel SSRI modes of action warrant consideration in antidepressant drug development efforts.

Thu, 4 Jul 2013 12:00:00 +0100 http://edoc.ub.uni-muenchen.de/16058/ http://edoc.ub.uni-muenchen.de/16058/1/Geberl_Cornelia.pdf Geberl, Cornelia Graduate School of Systemic Neurosciences (GSN)

Mon, 24 Jun 2013 12:00:00 +0100 http://edoc.ub.uni-muenchen.de/15953/ http://edoc.ub.uni-muenchen.de/15953/1/Wiese_Eva.pdf Wiese, Eva Graduate School of Systemic Neurosciences (GSN) 0

Age-related cognitive decline has been linked to a reduction in attentional resources that are assumed to result from alterations in the aging brain. A core ability that is subject to age-related decline is visual attention, which enables individuals to select the most important information for conscious processing and action. However, visual attention is considered a conglomerate of various functions and the specific components underlying age differences in performance remain little understood. The present PhD project aimed at dissociating age effects on several (sub-) components that concur in visual attention tasks within a neurocognitive approach. Established and theoretically grounded psychological paradigms that allow separating various attentional components were combined with event-related potentials (ERPs), which provide a temporally fine-graded dissociation of cognitive processes involved in a task. 1st Project The first project was designed to determine the origin(s) of age-related decline in visual search, a key paradigm of attention research. To pursue this goal on a micro-level, response time measures in a compound-search task, in which the target-defining feature of a pop-out target (color/shape) was dissociated from the response-defining feature (orientation), were coupled with lateralized ERPs. Several ERP components tracked the timing of processing stages involved in this task, these being (1) allocation of attention to the target, marked by the posterior-contralateral negativity (PCN), (2) target analyses in vSTM, marked by the sustained posterior-contralateral negativity (SPCN), (3) response selection, marked by the stimulus-locked lateralized readiness potential (LRP) and (4) response execution, marked by the response-locked LRP. Slowed response times (RT) in older participants were associated with age differences in all analyzed ERPs, indicating that behavioural slowing accrues across multiple stages within the information processing stream. Furthermore, v behavioral data and ERPs were analyzed with respect to age and carry-over effects from one trial to the next. The intertrial analyses revealed relatively automatic processes – such as dimension weighting facilitating the early stage of visual selection, and response weighting facilitating the late stage of response execution – to be preserved in older age. By contrast, more controlled processes – such as the flexible stimulus-response (S-R) (re-) mapping across trials on the intermediate stages of response selection - were particularly affected by aging. This indicates that besides general slowing, specific age decrements in executively controlled processes contribute to age-related decline in visual search. 2nd Project The second project explored neural markers of individual and age differences in attention parameters formally integrated in Bundesen’s computational Theory of Visual Attention (TVA). According to the model, two parameters of general visual attention capacity, perceptual processing speed C and visual short-term memory (vSTM) storage capacity K are defined and can be modeled mathematically independently for a particular individual. More recently, the neural interpretation of the model (NTVA) suggested that the two functions (at least partly) rely on distinct brain mechanisms. To test this assumption in an empirical approach, individual TVA-based estimates were derived in a standard TVA whole report task, and ERPs of the same participants were recorded in an adapted EEG-compatible version of the task. In the first study of the second project, we explored neurophysiological markers of interindividual differences in the two functions in younger participants. The results revealed distinct ERP correlates to be related to the parameters: Individuals with higher compared to lower processing speed C had significantly smaller posterior N1 amplitudes, suggesting that the rate of object categorization is associated with the efficiency of early visual processing. Individuals with higher compared to lower storage capacity showed stronger contralateral delay activity (CDA) over visual areas, indicating that the limit of vi vSTM relies on topographically-organized sustained activation within the visual system. These results can be regarded as direct neuroscientific evidence for central assumptions of the theoretical framework. In the second study of the second project, the same approach was pursued to investigate whether and how TVA attentional capacity parameters and their neural markers change with aging. First, the same ERP correlates of processing speed and storage capacity indexing individual differences in younger participants (i.e., the posterior N1 marked differences in processing speed C and the CDA marked differences in storage capacity K, respectively) were found to be valid also in the older group. In addition to this, two further components marked performance differences in the parameters exclusively within the older group: Older participants with lower processing speed showed smaller anterior N1 amplitudes relative to faster older and all younger participants, suggesting a selective loss of resources supporting early control of attentional guidance. Older participants with higher storage capacity exhibited a stronger right-central positivity than older participants with lower storage capacity and all younger participants. This pattern is indicative of compensatory recruitment of additional neural resources in high-functioning older individuals, presumably related to enhanced executive control fostering sustained activation of vSTM representations. Again, these findings strongly support the NTVA framework, proposing distinct neural mechanisms underlying processing speed and storage capacity. Furthermore, they show that distinct mechanisms of attentional control determine the two functions in older age.

Mon, 18 Mar 2013 12:00:00 +0100 http://edoc.ub.uni-muenchen.de/16087/ http://edoc.ub.uni-muenchen.de/16087/1/Kupferberg_Aleksandra.pdf Kupferberg, Aleksandra Graduate School of Systemic Neurosciences (GSN)

Anyone who has climbed a mountain before knows that the perceived distance walked depends on more than just its physical length. This intriguing relationship between physical and experienced magnitudes has fascinated researchers across various disciplines for more than 200 years. Part of the enthusiasm is driven by the fact that, although magnitudes, as well as the sensory organs with which we measure them, differ in so many ways, there are unifying principles in behavior common to all types of magnitudes estimated. In this thesis, the general characteristics of human magnitude estimation are studied in the case of visual path integration. The aim is to clarify the role of a-priori knowledge on the estimate of magnitude and to provide a unifying mathematical framework that explains the behavior. In particular, we investigated human linear and angular displacement estimation in different experimental situations with varying experience-dependent and abstract a-priori knowledge. We find systematic behavioral characteristics that are omnipresent in magnitude estimation studies, like the range effect, the regression effect or scalar variability. These characteristics are explained by a general model that combines a logarithmic scaling of magnitudes according to the Weber-Fechner law with the concept of Bayesian inference. The model incorporates apriori knowledge about the stimulus and updates this knowledge on a trial-by-trial basis. The resulting iterative Bayesian estimation accounts for the aforementioned behavioral characteristics and provides a link between the two most well-known laws in psychophysics: the Weber-Fechner and Stevens’ powerlaw. This work provides substantial evidence that magnitude estimation is not purely driven by sensation but underlies perceptual estimation processes that exploit and incorporate different types of information sources, in particular short-term prior experience. The proposed mathematical framework is likely applicable to magnitude estimation across different modalities and consequently contributes to a unifying account of the behavior.

The visual and vestibular systems play one of the central roles in the perception of verticality, spatial orientation, maintenance of balance and distinguishing self-motion from motion of the environment. As the brain continuously and simultaneously receives an enormous quantity of information through their receptor organs, collaboration between these systems at different levels of information processing is crucial for the proper execution of the above mentioned functions. Psychophysical and neuroimaging research in humans has provided support for the concept of a reciprocal inhibitory visual-vestibular interaction, the functional significance of which lies in suppression of potential mismatch between incongruent sensory inputs delivered from the two systems. Functional magnetic resonance imaging (fMRI) enabled visualization of this interaction through detection of blood-oxygen-level-dependant (BOLD) signal increases or signal decreases in the visual and vestibular networks during unisensory stimulation. Specifically, visual stimulation related to the percept of self-motion, such as optokinetic stimulation, was shown to elicit BOLD signal increases in areas involved in visual processing along with BOLD signal decreases in areas involved in vestibular processing. Increasing age was shown to alter the morphological and functional properties of the sensory, motor and cognitive systems. Previous research has revealed that senescence associates with deterioration of both, visual and vestibular functions, as well as a change in the psychophysical measurements related to their interaction. However, the effects of age on the BOLD signal pattern reflecting the visual-vestibular interaction have not yet been investigated. Exploring these effects in healthy subjects could offer the possibility to detect early age-related changes in the cortical function occurring before a decline in behavioural measurements can be detected. Aside broadening the scientific knowledge on the physiological changes with age in the sensory systems and their interactions, such research would also help to better understand the pathophysiological processes underlying various visual and vestibular disorders investigated in neuroimaging studies. Therefore, the aim of this doctoral thesis was to explore how the BOLD signal related to the visualvestibular interaction during optokinetic nystagmus (OKN) changes with age in healthy subjects. It specifically aimed to investigate the age-related changes in the spatial and temporal patterns of the signal during unaltered oculomotor performance. In order to obtain information on the diverse effects of age, the changes in the mean of the BOLD signal, as well as the changes in its temporal variability were analyzed. For the purpose of differentiating between global and task-related changes with age, the alterations of the BOLD signal during OKN were compared to the alterations of the BOLD signal elicited by a pure visual and a pure motor task. In the frame of this work, we were able to show that significant age-related changes in the mean of the BOLD signal and in its temporal fluctuations occur prior to any measurable decline in OKN performance. The changes in the mean of the BOLD signal were taskspecific and possibly reflected age-related alterations in neurovascular coupling and neural processing related to OKN. They were found only in cortical and subcortical areas of the visual system. The changes in the temporal fluctuations of the BOLD signal were not specific for the OKN task, but rather region-specific, affecting mostly areas know to be part of the multimodal vestibular processing network.

Thu, 20 Dec 2012 12:00:00 +0100 http://edoc.ub.uni-muenchen.de/15183/ http://edoc.ub.uni-muenchen.de/15183/1/Schuemann_Anne.pdf Schümann, Anne Graduate School of Systemic Neuroscien

’Gain-field-like’ tuning behavior is characterized by a modulation of the neuronal response depending on a certain variable, without changing the actual receptive field characteristics in relation to another variable. Eye position gain fields were first observed in area 7a of the posterior parietal cortex (PPC), where visually responsive neurons are modulated by ocular position. Analysis of artificial neural networks has shown that this type of tuning function might comprise the neuronal substrate for coordinate transformations. In this work, neuronal activity in the dorsal medial superior temporal area (MSTd) has been analyzed with an focus on it’s involvement in oculomotor control. MSTd is part of the extrastriate visual cortex and located in the PPC. Lesion studies suggested a participation of this cortical area in the control of eye movements. Inactivation of MSTd severely impairs the optokinetic response (OKR), which is an reflex-like kind of eye movement that compensates for motion of the whole visual scene. Using a novel, information-theory based approach for neuronal data analysis, we were able to identify those visual and eye movement related signals which were most correlated to the mean rate of spiking activity in MSTd neurons during optokinetic stimulation. In a majority of neurons firing rate was non-linearly related to a combination of retinal image velocity and eye velocity. The observed neuronal latency relative to these signals is in line with a system-level model of OKR, where an efference copy of the motor command signal is used to generate an internal estimate of the head-centered stimulus velocity signal. Tuning functions were obtained by using a probabilistic approach. In most MSTd neurons these functions exhibited gain-field-like shapes, with eye velocity modulating the visual response in a multiplicative manner. Population analysis revealed a large diversity of tuning forms including asymmetric and non-separable functions. The distribution of gain fields was almost identical to the predictions from a neural network model trained to perform the summation of image and eye velocity. These findings therefore strongly support the hypothesis of MSTd’s participation in the OKR control system by implementing the transformation from retinal image velocity to an estimate of stimulus velocity. In this sense, eye velocity gain fields constitute an intermediate step in transforming the eye-centered to a head-centered visual motion signal.Another aspect that was addressed in this work was the comparison of the irregularity of MSTd spiking activity during optokinetic response with the behavior during pure visual stimulation. The goal of this study was an evaluation of potential neuronal mechanisms underlying the observed gain field behavior. We found that both inter- and intra-trial variability were decreased with increasing retinal image velocity, but increased with eye velocity. This observation argues against a symmetrical integration of driving and modulating inputs. Instead, we propose an architecture where multiplicative gain modulation is achieved by simultaneous increase of excitatory and inhibitory background synaptic input. A conductance-based single-compartment model neuron was able to reproduce realistic gain modulation and the observed stimulus-dependence of neural variability, at the same time. In summary, this work leads to improved knowledge about MSTd’s role in visuomotor transformation by analyzing various functional and mechanistic aspects of eye velocity gain fields on a systems-, network-, and neuronal level.

Mon, 10 Dec 2012 12:00:00 +0100 http://edoc.ub.uni-muenchen.de/15188/ http://edoc.ub.uni-muenchen.de/15188/1/Deshpande_Aditi.pdf Deshpande, Aditi Graduate School of Systemic Neurosciences (GSN)

Sat, 8 Dec 2012 12:00:00 +0100 http://edoc.ub.uni-muenchen.de/13915/ http://edoc.ub.uni-muenchen.de/13915/1/Weber_Franz.pdf Weber, Franz Graduate School

Neurofascin (NF) is a cell-adhesion molecule that is found at the nodes of Ranvier. The 186 kDa isoform of neurofascin (NF186) is expressed on the axon in the exposed node, and the 155 kDa isoform (NF155) is expressed on myelinating glia at the paranode. NF186 is essential for clustering of sodium channels to the nodes while NF155 is needed for close paranodal interactions between myelinating glia and axons. The neurofascins are found in both the peripheral and central nervous system (PNS and CNS). NF-specific autoantibodies were identified in serum of multiple sclerosis (MS) patients using a proteomics approach with two-dimensional Western blotting of human myelin glycoproteins. A monoclonal antibody (mAb) specific for NF was shown to induce axonal injury in an animal model of MS, experimental autoimmune encephalomyelitis. This indicated that NF is a relevant autoantibody target in patients with inflammatory diseases of the nervous system (central and peripheral), but actual abundance of anti-NF autoantibodies is unknown. The objectives of the thesis were the following: 1) Develop assays to detect autoantibodies against human NF. 2) Determine the prevalence in patients with MS and with inflammatory diseases of the PNS. 3) Characterize the reactivity by immunoglobulin isotyping, serial dilution, epitope mapping, and staining of nodal structures in tissue sections. 4) Affinity purify anti-NF antibodies from plasma exchange material. 5) Determine possible in vivo effects of anti-NF antibodies in the PNS using a neuritis animal model. First, we expressed the complete human NF155 and NF186 on the surface of stable human cell lines, produced the complete extracellular portion of the NFs in HEK293 cells, and expressed truncated variants of the NFs in E. coli. With these reagents, we set up three antibody detection assays: cell-based assay by flow cytometry, ELISA, and Western blot. These assays were validated using NF-specific monoclonal and polyclonal antibodies, and optimized with a test cohort of serum samples. We screened 687 serum and 48 plasma exchange samples from patients with MS (n = 233), inflammatory diseases in the PNS (n = 294), and controls (n = 208). From serum analysis, we observed low prevalence of anti-NF reactivity (3%) by flow cytometry and/or ELISA despite broad reactivity in almost half of the serum samples analyzed by Western blot. Reactivity observed by flow cytometry and by ELISA were congruent only in the patients with the highest reactivities. The anti-NF antibodies were NF-isoform specific, mainly IgG subclasses, and at high titres in some cases. Using truncated variants of NF fused to super green fluorescence protein (sGFP), we showed that reactivity of anti-NF Abs was largely directed towards the membrane proximal extracellular domains that are unique to each isoform, while the membrane distal immunoglobulin-like domains and fibronectin domains were not recognized. A small proportion (3%; 8/254) of patients with GBS and CIDP showed reactivity to human NF by ELISA. A few showed a particularly high reactivity (up to 1:10 000 dilution) to NF. Two CIDP patients showed a particularly high (up to 1:10 000 dilution) anti-NF155 reactivity by FACS and ELISA, recognized paranodes in tissue sections, and exhibited dominant IgG4 subclass usage. Another CIDP patient who benefited from plasma exchange had a persistent anti-NF155 reactivity by ELISA in serum, and after affinity purification, anti-NF186 and -NF155 reactivity by FACS and ELISA were detected in addition. These antibodies were mainly IgG3, with minor contribution of IgM and IgA. To investigate possible functions of anti-NF antibodies in inflammatory PNS diseases, we injected two different monoclonal antibodies (mAbs) into a P2-peptide induced experimental autoimmune neuritis (EAN) animal model at disease onset. We found that while the anti-NF mAbs prolonged and exacerbated clinical disease in these animals, they could not induce disease on their own. We detected NF-reactivity in a small proportion of MS samples (3%; 7/225) by ELISA and flow cytometry. We obtained follow-up material from two NF-reactive patients and saw a persistent NF reactivity in one of them. To increase detection sensitivity, we affinity purified anti-NF antibodies from plasma exchange material of patients with MS (n = 8). IgG, IgM, and IgA were isolated from most of the samples; they were found to recognize NF155 and to a lower extent NF186 by ELISA and in a few also by flow cytometry. This indicates that low levels of anti-NF antibodies exist in a proportion of MS patients. In conclusion, 3% of serum samples from patients with PNS inflammatory neuropathies (GBS and CIDP) showed reactivity by ELISA and none of the controls. In an animal model of autoimmune peripheral nerve inflammation, we showed, using two anti-NF mAbs, that antibody targeting of NF can enhance and prolong disease course. This suggests that antibodies to NF may be relevant for a small group of patients with peripheral inflammatory neuropathies. In MS patients, 3% showed anti-NF reactivity by flow cytometry and ELISA. Furthermore, low levels of anti-NF antibodies that could be detected by ELISA and flow cytometry after affinity purification were additionally found in some MS patient samples that were unreactive by serum screening. This raises the possibility that low levels of antibodies to NF are present in some MS patients and may contribute to the pathogenesis of this chronic disease.

This thesis proposes a new approach to investigate insight problem solving. Introducing magic tricks as a problem solving task, we asked participants to find out the secret method used by the magician to create the magic effect. Based on the theoretical framework of the representational change theory, we argue that magic tricks are ideally suited to investigate insight because similar to established insight tasks like puzzles, observers’ prior knowledge activates constraints. In order to see through the magic trick, the constraints must be overcome by changing the problem representation. The aim of the present work is threefold: First, we set out to provide a proof of concept for this novel paradigm by demonstrating that it is actually possible for observers to gain insight into the magician’s secret method and that this can be experienced as a sudden, insightful solution. We therefore aimed at showing that magic tricks can trigger insightful solutions that are accompanied by an Aha! experience. The proposed paradigm could be a useful contribution to the field of insight research where new stimuli beyond traditional puzzle approaches are sorely needed. Second, the present work is aimed at contributing to a better understanding of the subjective Aha! experience that is currently often relied on as important classification criterion in neuroscientific studies of insight, yet remains conceptually vague. The new task will therefore be used to further elucidate the phenomenology of the Aha! experience by assessing participants’ individual solving experiences. As a third question, we investigated the influence of insight on memory. A positive impact of insight on subsequent solution recall is often implicitly assumed, because the representational change underlying insightful solutions is assumed to facilitate the retention of solution knowledge, yet this was never tested. A stimulus set of magic tricks was developed in collaboration with a professional magician, covering a large range of different magic effects and methods. After recording the tricks in a standardized theatre setting, pilot studies were run on 45 participants to identify appropriate tricks and to ensure that they were understandable, surprising and difficult. In the main experiment, 50 participants watched the final set of 34 magic tricks, with the task of trying to figure out how the trick was accomplished. Each trick was presented up to three times. Upon solving the trick, participants had to indicate whether they had found the solution through sudden insight (i.e. with an Aha! experience) or not. Furthermore, we obtained a detailed characterization of the Aha! experience by asking participants for a comprehensive quantitative (ratings on a visual analogue scale with fixed dimensions) and qualitative evaluation (free self-reports) which was repeated after 14 days to control for its reliability. At that time, participants were also required to perform a recall of their solutions. We found that 49% of all magic tricks could be solved and specifically, that insightful solutions were elicited in 41.1% of solved trials. In comparison with noninsight solutions, insightful solutions (brought about by representational change) were more likely to be correct and reached earlier. Quantitative evaluations of individual Aha! experiences turned out to be highly reliable since they remained identical across the time span of 14 days. Qualitatively, participants reported more emotional than cognitive aspects. This primacy of positive emotions was found in qualitative as well as in quantitative evaluations, although two different methods were used. We also found that experiencing insight leads to a facilitated recall of the respective solutions since 64.4% of all insight solutions were recalled correctly, whereas only 52.4% of all noninsight solutions were recalled correctly after a delay of 14 days. We demonstrated the great potential of our new approach by providing a proof of concept for magic tricks as a problem solving task and conclude that magic tricks offer a novel way of inducing problem solving that elicits insight. The reliability of individual evaluations of Aha! experiences indicates that, despite its subjective character, it can be justified to use the Aha! experience as a classification criterion. The present work contributes to a better understanding of the phenomenology of the Aha! experience by providing evidence for the occurrence of strong positive emotions as a prevailing aspect. This work also revealed a memory advantage for solutions that were reached through insight, demonstrating a facilitating effect of previous insight experiences on the recall of solutions. This finding provides support for the assumption that a representational change underlying insightful solving experiences leads to long-lasting changes in the representation of a problem that facilitate the retention of the problem’s solution. In sum, the novel approach presented in this thesis is shown to constitute a valuable contribution to the field of insight research and offers much potential for future research. Revealing the relationship between insight and magic tricks, the framework of the representational change theory is applied to a new domain and thus enlarged. Combining the novel task domain of magic tricks with established insight tasks might help to further elucidate the process of insight problem solving which is a characteristic and vital part of human thinking and yet so difficult to grasp.

Fri, 5 Oct 2012 12:00:00 +0100 http://edoc.ub.uni-muenchen.de/14901/ http://edoc.ub.uni-muenchen.de/14901/1/Hegenloh_Michael.pdf Hegenloh, Michael Graduate School of Systemic Neurosciences (G

Animals require cognitive maps for efficiently navigating in their natural habitat. Cognitive maps are a neuronal representation of their outside world. In mammals, place cells and grid cells have been implicated to form the basis of these neuronal representations. Place cells are active at one particular location in an environment and grid cells at multiple locations of the external world that are arranged in a hexagonal lattice.

The hippocampus is one of the regions in the mammalian brain that is associated with memory of events in their spatiotemporal context. Sequences of neuronal activity in the hippocampus are the chief candidate for a neurophysiological correlate of such contextual, or episodic memory. Simultaneously to replaying these behaviorally-related activity sequences, the hippocampus engages in a powerful and fast oscillation known as sharp-wave ripples (SWR). Ripples in turn participate in a brain-wide pattern of activity and may orchestrate the local strengthening of memories and their broadcasting to the cortex. In this Thesis, both memory sequences and ripple oscillations are studied in the light of the unifying hypothesis that the coordinated activation of a neuronal assembly represents an individual memory item in the sequences, and is at the same time responsible for the individual cycles in the oscillations. To test the hypothesis, we investigated SWR in vitro and in vivo in the mouse, using intracellular recordings of currents in CA1 pyramidal cells referenced to the local field potential. Expanding current hypotheses on SWR generation, we found powerful, well ripple-locked and spatially pervasive but CA1-local excitatory inputs, indicative of presynaptic assemblies of CA1 principal neurons. Combining a novel peeling reconstruction algorithm for synaptic currents with recordings at different holding potentials, we could for the first time unravel individual synaptic contributions during ripples. Analysis of the strikingly precise timing of currents demonstrated that inhibition aligns its phase to excitation over the course of a ripple. We carried on the dissection of ripples to the theoretical domain by incorporating the effect of inhibition into a mean field model of sequence replay. Using this model, we inquired what are the neuronal assembly size and inhibitory feedback strength that maximize the capacity of a hippocampal network to store memories, so that those memories can be successfully retrieved during ripple episodes. We found that a linearly coupled inhibitory population indeed helps increase storage capacity by dynamically stabilizing replay in an oscillatory manner for lower assembly sizes than in absence of inhibition. The findings about the temporal structure of neuronal activation during ripples complement our experimental observations. Collectively, they offer new insights on the physiology and function of sharp-wave ripples, paving the way for an integrated, continuous-time model of large networks of sparsely connected neurons that replay activity sequences concomitant to transient ensemble oscillations.

Thu, 19 Jul 2012 12:00:00 +0100 http://edoc.ub.uni-muenchen.de/14665/ http://edoc.ub.uni-muenchen.de/14665/2/Riedl_Valentin.pdf Riedl, Valentin Graduate School of Systemic Neurosciences (GSN)

Mon, 25 Jun 2012 12:00:00 +0100 http://edoc.ub.uni-muenchen.de/14589/ http://edoc.ub.uni-muenchen.de/14589/1/Fraedrich_Eva.pdf Fraedrich, Eva Graduate School of Systemic Neurosciences (GSN)

Mon, 21 May 2012 12:00:00 +0100 http://edoc.ub.uni-muenchen.de/14709/ http://edoc.ub.uni-muenchen.de/14709/1/Funk_Johanna.pdf Funk, Johanna Graduate School of Systemic Neurosciences (GSN)

Humans explore the world by moving in it, whether moving their whole body as during walking or driving a car, or moving their arm to explore the immediate environment. During movement, self-motion cues arise from the sensorimotor system comprising vestibular, proprioceptive, visual and motor cues, which provide information about direction and speed of the movement. Such cues allow the body to keep track of its location while it moves through space. Sensorimotor signals providing self-motion information can therefore serve as a source for spatial processing in the brain. This thesis is an inquiry into human brain systems of movement and motion processing in a number of different sensory and motor modalities using functional magnetic resonance imaging (fMRI). By characterizing connections between these systems and the spatial representation system in the brain, this thesis investigated how humans understand space by moving through it. In the first study of this thesis, the recollection networks of whole-body movement were explored. Brain activation was measured during the retrieval of active and passive self-motion and retrieval of observing another person performing these tasks. Primary sensorimotor areas dominated the recollection network of active movement, while higher association areas in parietal and mid-occipital cortex were recruited during the recollection of passive transport. Common to both self-motion conditions were bilateral activations in the posterior medial temporal lobe (MTL). No MTL activations were observed during recollection of movement observation. Considering that on a behavioral level, both active and passive self-motion provide sufficient information for spatial estimations, the common activation in MTL might represent the common physiological substrate for such estimations. The second study investigated processing in the 'parahippocampal place area' (PPA), a region in the posterior MTL, during haptic exploration of spatial layout. The PPA in known to respond strongly to visuo-spatial layout. The study explored if this region is processing visuo-spatial layout specifically or spatial layout in general, independent from the encoding sensory modality. In both a cohort of sighted and blind participants, activation patterns in PPA were measured while participants haptically explored the spatial layout of model scenes or the shape of information-matched objects. Both in sighted and blind individuals, PPA activity was greater during layout exploration than during object-shape exploration. While PPA activity in the sighted could also be caused by a transformation of haptic information into a mental visual image of the layout, two points speak against this: Firstly, no increase in connectivity between the visual cortex and the PPA were observed, which would be expected if visual imagery took place. Secondly, blind participates, who cannot resort to visual imagery, showed the same pattern of PPA activity. Together, these results suggest that the PPA processes spatial layout information independent from the encoding modality. The third and last study addressed error accumulation in motion processing on different levels of the visual system. Using novel analysis methods of fMRI data, possible links between physiological properties in hMT+ and V1 and inter-individual differences in perceptual performance were explored. A correlation between noise characteristics and performance score was found in hMT+ but not V1. Better performance correlated with greater signal variability in hMT+. Though neurophysiological variability is traditionally seen as detrimental for behavioral accuracy, the results of this thesis contribute to the increasing evidence which suggests the opposite: that more efficient processing under certain circumstances can be related to more noise in neurophysiological signals. In summary, the results of this doctoral thesis contribute to our current understanding of motion and movement processing in the brain and its interface with spatial processing networks. The posterior MTL appears to be a key region for both self-motion and spatial processing. The results further indicate that physiological characteristics on the level of category-specific processing but not primary encoding reflect behavioral judgments on motion. This thesis also makes methodological contributions to the field of neuroimaging: it was found that the analysis of signal variability is a good gauge for analysing inter-individual physiological differences, while superior head-movement correction techniques have to be developed before pattern classification can be used to this end.

The medial superior olive (MSO) is an auditory brainstem nucleus within the superior olivary complex. Its functional role for sound source localization has been thoroughly investigated (for review see Grothe et al., 2010). However, few quantita tive data about the morphology of these neuronal coincidence detectors are available and computational models incorporating detailed reconstructions do not exist. This leaves open questions about metric characteristics of the morphology of MSO neurons as well as about electrophysiological properties that can be discovered using detailed multicompartmental models: what are the passive parameters of the membrane? What is the axial resistivity? How do dendrites integrate synaptic events? Is the medial dendrite symmetric to the lateral dendrite with respect to integration of synaptic events? This thesis has two main aspects: on the one hand, I examined the shape of a MSO neuron by developing and applying various morphological quantifications. On the other hand, I looked at the impact of morphology on basic electrophysiological properties and on characteristics of coincidence detection. As animal model I used Mongolian gerbils (Meriones unguiculatus) during the late phase of development between postnatal day 9 (P9) and 37 (P37). This period of time is of special interest, as it spans from just before hearing onset at P12 – P13 (Finck et al., 1972; Ryan et al., 1982; Smith and Kraus, 1987) to adulthood. I used single cell electroporation, microscopic reconstruction, and compartmentalization to extract anatomical parameters of MSO neurons, to quantitatively describe their morphology and development, and to establish multi-compartmental models. I found that maturation of the morphology is completed around P27, when the MSO neurons are morphologically compact and cylinder-like. Dendritic arbors become less complex between P9 and P21 as the number of branch points, the total cell length, and the amount of cell membrane decrease. Dendritic radius increases until P27 and is likely to be the main source of the increase in cell volume. In addition, I showed that in more than 85% of all MSO neurons, the axonal origin is located at the soma. I estimated the axial resistivity (80 Ω·cm) and the development of the resting conductance (total conductance during the state of resting potential) which reaches 3 mS/cm2 in adult gerbils. Applying these parameters, multi-compartmental models showed that medial versus lateral dendritic trees do not equally integrate comparable synaptic inputs. On average, latencies to peak and rise times of lateral stimulation are longer (12 μs and 5 μs, respectively) compared to medial stimulation. This is reflected in the fact that volume, surface area, and total cell length of the lateral dendritic trees are significantly more larger in comparison to the medial ones. Simplified models of MSO neurons showed that dendrites improve coincidence detection (Agmon-Snir et al., 1998; Grau-Serrat et al., 2003; Dasika et al., 2007). Here, I confirmed these findings also for multi-compartmental models with biological realistic morphologies. However, the improvement of coincidence detection by dendrites decreases during early postnatal development.

Thu, 12 Jan 2012 12:00:00 +0100 http://edoc.ub.uni-muenchen.de/14767/ http://edoc.ub.uni-muenchen.de/14767/1/Behrendt_Mona_Gwendolyn.pdf Behrendt, Mona Gwendolyn Graduate School of Systemic N

Fri, 16 Dec 2011 12:00:00 +0100 http://edoc.ub.uni-muenchen.de/14476/ http://edoc.ub.uni-muenchen.de/14476/1/Singh_Arun.pdf Singh, Arun Graduate Sch

Fri, 6 May 2011 12:00:00 +0100 http://edoc.ub.uni-muenchen.de/13052/ http://edoc.ub.uni-muenchen.de/13052/1/Couchman_Kiri.pdf Couchman, Kiri Graduate School of Systemic Neurosciences (GSN)

Tue, 1 Feb 2011 12:00:00 +0100 http://edoc.ub.uni-muenchen.de/13480/ http://edoc.ub.uni-muenchen.de/13480/1/Donatas_Jonikaitis.pdf Jonikaitis, Donatas Graduate School of Systemic Neurosciences (GSN)

Thu, 25 Nov 2010 12:00:00 +0100 http://edoc.ub.uni-muenchen.de/13116/ http://edoc.ub.uni-muenchen.de/13116/1/Roessert_Christian_A.pdf Rössert, Christian Andreas Graduate School of Systemic Neurosciences (GSN)

Tue, 19 Oct 2010 12:00:00 +0100 http://edoc.ub.uni-muenchen.de/13528/ http://edoc.ub.uni-muenchen.de/13528/1/Rangelov_Dragan.pdf Rangelov, Dragan Graduate School of Systemic Neurosciences (GSN)

Aside from recognizing and distinguishing sound patterns, the ability to localize sounds in the horizontal plane is an essential component of the mammalian auditory system. It facilitates approaching potential mating partners and allows avoiding predators. The superior olivary complex (SOC) within the auditory brainstem is the first site of binaural interaction and its major projections and inputs are well investigated. The adult input pattern, however, is not set from the beginning but changes over the period of development. Mammals including humans experience different stages and conditions of hearing during auditory development. The human brain for instance has to perform a transition after birth from the perception of sound waves transmitted in amniotic fluid to the perception of airborne sounds. Furthermore, small mammals like rodents, which are common model organisms for auditory research, perceive airborne sounds for the first time some days after birth, when their ear canals open. The basic neuronal projections and the intrinsic properties of neurons, such as the expression of specific ion channels, are already established and adjusted in the SOC during the perinatal period of partial deafness. An additional refinement of inputs and further adaptations of intrinsic characteristics occur with the onset of hearing in response to the new acoustic environment. It is likely that with ongoing maturation well-established inputs within the sound localization network need these adaptations to balance anatomical changes such as an increasing head size. In addition, short-term adjustments of synaptic inputs in the adult auditory system are equally necessary for a faithful representation of auditory space. A recent study suggests that these short-term adaptations are partially represented at the auditory brainstem level. The question of how intrinsic properties change during auditory development, to what extent auditory experience is involved in these changes and the functional implications of these changes on the sound localization circuitry is only partially answered. I used the hyperpolarization-activated and cyclic nucleotide-gated cation channels (HCN channels), which are a key determinant of the intrinsic properties of auditory brainstem neurons, as a target to study the influence of auditory experience on the intrinsic properties of neurons in the auditory brainstem. Another important question still under discussion is how neurons in the auditory brainstem might fine-tune their firing behavior to cope optimally with an altered acoustic environment. Recent data suggest that auditory processing is also affected by modulatory mechanisms at the brainstem level, which for instance change the input strength and thus alter the spike output of these neurons. One possible candidate is the metabotropic GABAB receptor (GABABR) which has been shown to be abundant in the adult auditory brainstem, although GABAergic projections are scarce in the mature auditory brainstem. These questions were investigated by performing whole-cell patch-clamp recordings of SOC neurons from Mongolian gerbils at different developmental stages in the acute brain slice preparation. Specific currents and receptors were isolated using pharmacological means. Immmunohistochemical results additionally supported physiological findings. In the first study, I investigated the developmental regulation of HCN channels in the SOC and their underlying depolarizing current Ih, which has been shown to regulate the excitability of neurons and to enhance the temporally precise analysis of binaural acoustic cues. I characterized the developmental changes of Ih in neurons of the lateral superior olive (LSO) and the medial nucleus of the trapezoid body (MNTB), which in the adult animals show different HCN subunit composition. I showed that right after hearing onset there was a strong increase of Ih in the LSO and just a minor increase in the MNTB. In addition, the open probability of HCN channels was shifted towards more positive voltages in both nuclei and the activation time constants accelerated during the first days of auditory experience. These results implicate that Ih is actively regulated by sensory input activity. I tested this hypothesis by inducing auditory deprivation which was achieved by surgically removing the cochlea in gerbils before hearing onset. The effect was opposite in neurons of the MNTB and the LSO. Whereas in LSO neurons auditory deprivation resulted in increased Ih amplitude, MNTB neurons displayed a moderate decrease in Ih. These results suggest that auditory experience differentially changes the amount of HCN channels dependent on the subunit composition or possibly alters intracellular cAMP levels, thereby shifting the voltage dependence of Ih. This regulatory mechanism might thus maintain adequate excitability levels within the SOC. A second study was carried out to investigate the role of GABABRs in the medial superior olive (MSO). Upon activation, these metabotropic receptors are known to decrease the release probability of neurotransmitters at the presynapse thereby altering excitatory and inhibitory currents at the postsynaptic site. Neurons in the MSO analyze interaural time differences (ITDs) by comparing the relative timing of the excitatory inputs from the two ears using a coincidence mechanism. In addition, these neurons receive a precisely timed inhibitory input from each ear which shifts ITDs in the physiological relevant range. Since the major inhibitory input changes its transmitter type from mixed GABA/glycinergic to only glycinergic after hearing onset it was now interesting to examine the mediated effects of GABABRs, which have been shown to be abundant in the prehearing and adult MSO of gerbils. Furthermore, revealing the precise expression pattern of GABABRs and their influence on excitatory and inhibitory currents in the MSO during auditory development should provide further evidence of their functional relevance. Performing pharmacological experiments I could now demonstrate that the activation of GABABRs before hearing onset decreases the current of excitatory inputs stronger than that of inhibitory inputs whereas a switch is performed after hearing onset and inhibitory currents are stronger decreasedcompared to excitatory currents. In a similar way, also the expression pattern of GABABRs changes before and after hearing onset as revealed by immunohistochemistry. Since the main inhibitory inputs to the adult MSO are purely glycinergic, it was commonly assumed that GABABRs occupy only a minor role in the mature auditory brainstem. Contradictory to this, it was possible to activate presynaptic GABABRs by synaptic stimulation even in adult animals and to observe a profound decrease of inhibitory current in MSO neurons. These results suggest GABAergic projections of yet unknown origin targeting the MSO. It is therefore quite likely that GABABRs modulate and possibly improve the localization of low frequency sounds even in adult mammals. Summarized, the outcome of this thesis contributes to a better understanding of the developmental adaptation in the auditory system and demonstrates that the orderly specification of intrinsic properties within the SOC is dependent on auditory experience. Moreover, I show that even in mature animals the synaptic strength of MSO inputs can be modulated by synaptic GABA release. This should emphasize the importance of modulatory mechanisms and could be the basis for future studies concerning the field of sound localization.