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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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Emergent coordination or movement synchronization is an often observed phenomenon in human behavior. Humans synchronize their gait when walking next to each other, they synchronize their postural sway when standing closely, and they also synchronize their movement behavior in many other situations of daily life. Why humans are doing this is an important question of ongoing research in many disciplines: apparently movement synchronization plays a role in children’s development and learning; it is related to our social and emotional behavior in interaction with others; it is an underlying principle in the organization of communication by means of language and gesture; and finally, models explaining movement synchronization between two individuals can also be extended to group behavior. Overall, one can say that movement synchronization is an important principle of human interaction behavior. Besides interacting with other humans, in recent years humans do more and more interact with technology. This was first expressed in the interaction with machines in industrial settings, was taken further to human-computer interaction and is now facing a new challenge: the interaction with active and autonomous machines, the interaction with robots. If the vision of today’s robot developers comes true, in the near future robots will be fully integrated not only in our workplace, but also in our private lives. They are supposed to support humans in activities of daily living and even care for them. These circumstances however require the development of interactional principles which the robot can apply to the direct interaction with humans. In this dissertation the problem of robots entering the human society will be outlined and the need for the exploration of human interaction principles that are transferable to human-robot interaction will be emphasized. Furthermore, an overview on human movement synchronization as a very important phenomenon in human interaction will be given, ranging from neural correlates to social behavior. The argument of this dissertation is that human movement synchronization is a simple but striking human interaction principle that can be applied in human-robot interaction to support human activity of daily living, demonstrated on the example of pick-and-place tasks. This argument is based on five publications. In the first publication, human movement synchronization is explored in goal-directed tasks which bare similar requirements as pick-and-place tasks in activities of daily living. In order to explore if a merely repetitive action of the robot is sufficient to encourage human movement synchronization, the second publication reports a human-robot interaction study in which a human interacts with a non-adaptive robot. Here however, movement synchronization between human and robot does not emerge, which underlines the need for adaptive mechanisms. Therefore, in the third publication, human adaptive behavior in goal-directed movement synchronization is explored. In order to make the findings from the previous studies applicable to human-robot interaction, in the fourth publication the development of an interaction model based on dynamical systems theory is outlined which is ready for implementation on a robotic platform. Following this, a brief overview on a first human-robot interaction study based on the developed interaction model is provided. The last publication describes an extension of the previous approach which also includes the human tendency to make use of events to adapt their movements to. Here, also a first human-robot interaction study is reported which confirms the applicability of the model. The dissertation concludes with a discussion on the presented findings in the light of human-robot interaction and psychological aspects of joint action research as well as the problem of mutual adaptation. / Spontan auftretende Koordination oder Bewegungssynchronisierung ist ein häufig zu beobachtendes Phänomen im Verhalten von Menschen. Menschen synchronisieren ihre Schritte beim nebeneinander hergehen, sie synchronisieren die Schwingbewegung zum Ausgleich der Körperbalance wenn sie nahe beieinander stehen und sie synchronisieren ihr Bewegungsverhalten generell in vielen weiteren Handlungen des täglichen Lebens. Die Frage nach dem warum ist eine Frage mit der sich die Forschung in der Psychologie, Neuro- und Bewegungswissenschaft aber auch in der Sozialwissenschaft nach wie vor beschäftigt: offenbar spielt die Bewegungssynchronisierung eine Rolle in der kindlichen Entwicklung und beim Erlernen von Fähigkeiten und Verhaltensmustern; sie steht in direktem Bezug zu unserem sozialen Verhalten und unserer emotionalen Wahrnehmung in der Interaktion mit Anderen; sie ist ein grundlegendes Prinzip in der Organisation von Kommunikation durch Sprache oder Gesten; außerdem können Modelle, die Bewegungssynchronisierung zwischen zwei Individuen erklären, auch auf das Verhalten innerhalb von Gruppen ausgedehnt werden. Insgesamt kann man also sagen, dass Bewegungssynchronisierung ein wichtiges Prinzip im menschlichen Interaktionsverhalten darstellt. Neben der Interaktion mit anderen Menschen interagieren wir in den letzten Jahren auch zunehmend mit der uns umgebenden Technik. Hier fand zunächst die Interaktion mit Maschinen im industriellen Umfeld Beachtung, später die Mensch-Computer-Interaktion. Seit kurzem sind wir jedoch mit einer neuen Herausforderung konfrontiert: der Interaktion mit aktiven und autonomen Maschinen, Maschinen die sich bewegen und aktiv mit Menschen interagieren, mit Robotern. Sollte die Vision der heutigen Roboterentwickler Wirklichkeit werde, so werden Roboter in der nahen Zukunft nicht nur voll in unser Arbeitsumfeld integriert sein, sondern auch in unser privates Leben. Roboter sollen den Menschen in ihren täglichen Aktivitäten unterstützen und sich sogar um sie kümmern. Diese Umstände erfordern die Entwicklung von neuen Interaktionsprinzipien, welche Roboter in der direkten Koordination mit dem Menschen anwenden können. In dieser Dissertation wird zunächst das Problem umrissen, welches sich daraus ergibt, dass Roboter zunehmend Einzug in die menschliche Gesellschaft finden. Außerdem wird die Notwendigkeit der Untersuchung menschlicher Interaktionsprinzipien, die auf die Mensch-Roboter-Interaktion transferierbar sind, hervorgehoben. Die Argumentation der Dissertation ist, dass die menschliche Bewegungssynchronisierung ein einfaches aber bemerkenswertes menschliches Interaktionsprinzip ist, welches in der Mensch-Roboter-Interaktion angewendet werden kann um menschliche Aktivitäten des täglichen Lebens, z.B. Aufnahme-und-Ablege-Aufgaben (pick-and-place tasks), zu unterstützen. Diese Argumentation wird auf fünf Publikationen gestützt. In der ersten Publikation wird die menschliche Bewegungssynchronisierung in einer zielgerichteten Aufgabe untersucht, welche die gleichen Anforderungen erfüllt wie die Aufnahme- und Ablageaufgaben des täglichen Lebens. Um zu untersuchen ob eine rein repetitive Bewegung des Roboters ausreichend ist um den Menschen zur Etablierung von Bewegungssynchronisierung zu ermutigen, wird in der zweiten Publikation eine Mensch-Roboter-Interaktionsstudie vorgestellt in welcher ein Mensch mit einem nicht-adaptiven Roboter interagiert. In dieser Studie wird jedoch keine Bewegungssynchronisierung zwischen Mensch und Roboter etabliert, was die Notwendigkeit von adaptiven Mechanismen unterstreicht. Daher wird in der dritten Publikation menschliches Adaptationsverhalten in der Bewegungssynchronisierung in zielgerichteten Aufgaben untersucht. Um die so gefundenen Mechanismen für die Mensch-Roboter Interaktion nutzbar zu machen, wird in der vierten Publikation die Entwicklung eines Interaktionsmodells basierend auf Dynamischer Systemtheorie behandelt. Dieses Modell kann direkt in eine Roboterplattform implementiert werden. Anschließend wird kurz auf eine erste Studie zur Mensch- Roboter Interaktion basierend auf dem entwickelten Modell eingegangen. Die letzte Publikation beschreibt eine Weiterentwicklung des bisherigen Vorgehens welche der Tendenz im menschlichen Verhalten Rechnung trägt, die Bewegungen an Ereignissen auszurichten. Hier wird außerdem eine erste Mensch-Roboter- Interaktionsstudie vorgestellt, die die Anwendbarkeit des Modells bestätigt. Die Dissertation wird mit einer Diskussion der präsentierten Ergebnisse im Kontext der Mensch-Roboter-Interaktion und psychologischer Aspekte der Interaktionsforschung sowie der Problematik von beiderseitiger Adaptivität abgeschlossen.

Introduction: Successful storage of memory can be divided into three fundamental processes: encoding, consolidation and retrieval. During encoding, information is acquired e.g. in a learning session of an experiment. New mnemonic traces are formed in the brain. When the information needs to be remembered e.g. at the retrieval session of an experiment, memory needs to be recovered. Since encoding does not lead to instantaneous permanent storage of the learned material, a form of memory stabilization is necessary. A person’s freshly acquired memory is initially fragile until the memory trace is reinforced through a process of consolidation. While learning and retrieval must occur during wakefulness, memory consolidation can occur during sleep. One question that is still under debate in sleep literature is whether a period of sleep, in comparison to wakefulness, significantly and persistently benefits the consolidation of recently and explicitly acquired declarative information (such that memory retrieval after a period of sleep is significantly better than retrieval after a period of wakefulness). A further problem regarding the benefit of sleep for memory is the discrepancy between functional and behavioral findings: Sleep associated changes are possibly a covert process and changes on the anatomical level are not necessarily congruent with behavioral results. Another question concerns memory consolidation in the long run. In humans, the medial temporal lobe, especially the hippocampus, is an important brain structure involved in declarative memory retrieval. Through the process of consolidation, declarative memory has been found to become independent of the hippocampus over time. Yet, human imaging studies investigating memory retrieval for a longer period of time (several months) are scarce. Another gap of knowledge lies in the role of the hippocampus. Several different hypotheses about its role exist: The multiple trace theory, established by Nadel and Moscovitch (1997), states that personally experienced episodes stay hippocampus dependent, whereas semanticized memories become independent over time. O’Keefe et al. (1978) proposed that the hippocampus is permanently accessed for spatial memory retrieval. According to Eichenbaum (2000), the hippocampus binds new information coupled with an episode into a network of existing memory traces. This thesis focuses on long-term memory. The major focus lies on declarative memory, whereas the minor focus lies on non-declarative memory. All five studies of this thesis investigate declarative memory and the last study (study 5) additionally investigates non-declarative memory. Study 1: Objective: To investigate the relation between episodic (declarative) memory and sleep versus sleep deprivation on the functional and behavioral level. The aim is to do the investigation on a time scale of 2 ½ months. Methods: The analysis was based on a between-group (factor: sleep / wake), within-subject (factor: autobiographical task / spatial task) design. Each subject learned two episodic memory tasks (word associations): an autobiographical task and a spatial task. Brain activity (using a 3T MRT) and behavioral performances were measured at 3 times: 1) Immediately after learning; 2) after a night of sleep/wake and two recovery nights of sleep; 3) 2 ½ months after learning. Results: No sleep related changes in hippocampal activation could be concluded from the neuroimaging results. Supporting this, behavioral results (free recall) showed no difference between sleep and sleep deprivation groups. Recall results showed no difference between the sleep group and the sleep deprivation group. Study 2: Presuming that sleep supports hippocampus dependent declarative memory, but given the results of study 1, it was important to investigate the role of the hippocampus. Objective: This study focused on the role of the hippocampus in declarative memory retrieval, given the different hypotheses (mentioned above) about its role. Methods: Using a between-group design, hippocampal involvement during free recall at an early stage after encoding was compared between sequential, spatial and autobiographical learning strategies. (Study 2 was not a sleep-study). Free recall performance of concrete nouns was measured on the functional as well as behavioral level. Results: Not all episodic memory traces depended equally on the hippocampus when information was retrieved in free recall: Whereas recall of autobiographical memory relied on the hippocampus after consolidation, recall of spatially and sequentially associated information did not. Functional conjunction analyses showed that brain areas mutually involved in all tasks tested, were: the precuneus (medial parietal cortex), medial occipital gyrus and superior parietal lobe (SPL). Studies 3 – 5: The specific mechanisms underlying the process of memory consolidation are still not clarified. It has been suggested that a positive effect of sleep on memory occurs when a sensitive set of requirements is met, although to date, pinpointing the exact requirements has not been possible from sleep literature. Study 3: Objective: The question to be answered was: Is the type of retrieval, that is, cued recall or recognition, crucial for an effect of sleep on declarative memory? Methods: The following parameters were applied: i) Cued recall and recognition as the type of retrieval test; ii) Circadian rhythm: Learning either in the morning or in the evening; iii) The retention period between learning and the post-conditional test was kept constant at 12 hours; iv) Interference learning was used; v) The learning material was restricted to non-sense syllables. Results: A beneficial effect of sleep on memory retrieval 12 hours after learning non-sense syllables occurred only when syllables were tested via cued recall. However, results were influenced by circadian rhythm effects with better test scores in the morning than in the evening. Study 4: Objective: Same as in study 3, but controlling for the circadian rhythm effects by using nap sleep instead of nocturnal sleep. Methods: Circadian rhythm effects were controlled by choosing a 60 minute nap sleep paradigm, in which encoding and retrieval both took place at the same time of day (in the afternoon), for both the sleep and wake conditions. The two types of retrieval in relation to nap sleep and wakefulness were examined: cued recall and recognition. The following parameters were applied: i) Cued recall and recognition for the type of retrieval test; ii) Circadian rhythm: Learning in the afternoon; iii) The retention period between learning and the post-conditional test was kept constant at three hours (including a 60 minute nap or time spent awake); iv) Interference learning was used; v) The learning material consisted of concrete German nouns. Results: subjects did not perform significantly better after a period of napping compared to a period of wakefulness, neither for words tested via cued recall nor words tested via recognition. A sleep benefit on the behavioral level did not show to be specific to the type of retrieval test. Study 5: Objective: To examine whether a sleep benefit occurs between a critical period of 12 to 144 hours post learning. In addition to declarative memory, the relation between sleep and procedural memory is tested, using a motor sequence (finger tapping) task. Methods: Subjects learned a procedural and a declarative task. The following parameters were applied: i) Free recall for the declarative and procedural retrieval tests; ii) In contrast to the other studies, total sleep deprivation and daytime wakefulness were used as wake condition iii) The retention period between learning and testing was 12, 72 or 144 hours (3 groups); iv) Interference learning was not used for the declarative task (a main and new motor sequence task were learned); v) The learning material was restricted to non-sense syllables. Results: No beneficial post-learning effect of sleep could be detected in the declarative and procedural tasks over the retention interval of up to six days. Results of study 5 demonstrated that sleep after learning did not lead to better performance of motor skills than wakefulness after learning. Conclusion: From the results of the five studies of this thesis, it can be concluded that declarative and procedural memories are consolidated equally well over a period of wakefulness compared to a period of sleep. The type of retrieval, circadian rhythm, retention period, interference, and the type of material might all contribute to a set of variables influencing the benefit of sleep on memory. It can also be assumed that the human brain is capable of compensating a night of sleep deprivation without significant behavioral deficits during retrieval of verbal declarative and motor skill tasks, whether memory is tested shortly after encoding (a few hours), after days or after months.

Epilepsy is one of the most common chronic neurological diseases worldwide and the prevention of epileptogenesis is so far unmet. A major challenge in epilepsy research is the development of new therapeutic approaches for patients with therapy-resistant epilepsies, for epilepsy prevention and for disease modification. The endocannabinoid system serves as a retrograde negative feedback mechanism and one of its key functions is regulating neuronal activity within the central nervous system. Thus, the endocannabinoid system can be considered a putative target for central nervous system diseases including epilepsies. The purpose of this thesis was to evaluate the impact of the endocannabinoid and endovanilloid systems on both epileptogenesis and ictogenesis. Therefore, I modulated the systems pharmacologically and genetically and analyzed the impact on the generation of a hyperexcitable neuronal network as well as on ictogenesis in the kindling model of temporal lobe epilepsy. In addition, the impact of seizures on associated cellular alterations, like CB1-receptor (CB1R) expression and neurogenesis, was evaluated. I established that the endocannabinoid system affects seizure and afterdischarge duration dependent on the neuronal subpopulation being modulated. Genetic deletion of CB1Rs from GABAergic forebrain neurons caused shorter seizure duration. Deletion of CB1R from principal neurons of the forebrain and pharmacological antagonism with rimonabant (5 mg/kg) resulted in the opposite effect. Along with these findings, the CB1R density was increased in mice with recurrent induced seizures. However, neither genetic knockout nor pharmacological antagonism had any impact on the development of generalized seizures. In contrast to genetic deletion or pharmacological blockade of CB1Rs, modulation of transient receptor potential vanilloid receptor 1 (TRPV1) neither genetically nor pharmacologically with SB366791 (1 mg/kg) had an effect on the duration of behavioral or electrographic seizure activity. Pharmacological blockade of the 2-arachidonoylglycerol degrading enzyme, monoacylglycerol lipase (MAGL) with JZL184 (8 mg/kg), delayed the development of generalized seizures and decreased seizure and afterdischarge durations whereas in fully-kindled mice JZL184 (4, 8 and 16 mg/kg) had no relevant effects on associated seizure parameters. In addition, I confirmed by the use of conditional CB1R knockout mice that these effects are CB1R mediated. In conclusion, my findings support the concept that the endocannabinoid system may be a therapeutic target for decreasing seizure duration and that it is involved in terminating seizures as an endogenous mechanism. Moreover, targeting MAGL may be a promising strategy for an antiepileptogenic approach. Respective strategies are of particular interest for the management of long-lasting refractory status epilepticus and cluster seizures as well as for the prevention of the development of symptomatic epilepsies after an initial insult.

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Adult neurogenesis has been the focus of over 1500 articles in the past 10 years. Evidence for the continuous production of new neurons in the adult brain has raised hopes for new therapeutic approaches. On the other hand, the generation of new neurons is modulated in several neurological diseases and disorders, suggesting the involvement of the adult neurogenesis in their pathogenesis. Therefore, a better understanding of the disease-associated modulation of adult neurogenesis is essential for determining the most effective therapeutic strategy. The purpose of this doctoral project was to investigate long-term adult hippocampal neurogenesis changes in two disease models. BrdU labeling in combination with various cellular markers, and genetic fate-mapping approach were used to reach this goal. In the first experiment, the impact of the BeAN strain of the Theiler’s virus on hippocampal cell proliferation and neuronal progenitors was evaluated in two mouse strains which differ in the disease course. It was shown that Theiler’s murine encephalomyelitis virus can exert delayed effects on the hippocampal neurogenesis with long-term changes evident 90 days following the infection. The hippocampal changes proved to depend on strain susceptibility and might have been affected by microglial cells. In the second experiment, hippocampal neurogenesis was analyzed based on genetic fate mapping of transgenic animals in the amygdala-kindling model of epilepsy. The number of new granule neurons added to the dentate gyrus was increased in kindled animals. A prior seizure history proved to be sufficient to induce a long-term net effect on neuron addition and an ongoing occurrence of seizures did not further increase the number of new neurons. Hypertrophic astrocytes were observed in the kindled animals suggesting that seizures result in structural changes of astrocytes that could be detected long after the termination of the insults. The results of the experiments indicated the importance of methodological considerations in chronic studies of neurogenesis.