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.

No description available.

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.

Alzheimer’s disease (AD) is a fast growing global problem. AD is a form of dementia characterised by the progressive loss of cognitive abilities. Pathologically, the disease is defined by two neuropathological hallmarks: neurofibrillary tangles and amyloid-β plaques. Plaques appear to be toxic to brain tissue and are surrounded by activated microglia and astrocytes, dystrophic neurites and neurons under oxidative stress. When plaques first develop, they are generally small, but in advanced AD, plaques can be much larger. How small plaques may develop into large plaques is still unclear. A number of studies have shown that small plaques grow uniformly over time to give rise to larger plaques. However, this study investigates an alternative hypothesis: that clusters of multiple small plaques merge over time to form large plaques. This hypothesis was inspired by a study that showed that plaques do not deposit in random locations within the brain parenchyma, but rather form in clusters and that these plaque clusters get bigger over time. The aim was to investigate the clustering of plaques in vivo, and follow these clusters over time to see whether they merge together to form a single, larger plaque. This study employed a 2-stage staining technique to follow individual plaques in APPPS1 transgenic mice over time. The fluorescent, amyloid-binding dye Methoxy-X04 was injected into the mice at Day 0 of the experiment. Methoxy-X04 crosses the blood brain barrier and binds stably to plaques for several months and thus labelled the original plaque population. Following 1 day, 1 month or 4 month incubation periods, acute in vivo plaque imaging was performed or the mice sacrificed for post mortem analysis. Antibodies against amyloid-β labelled the state of the plaques at these later time points. Hence this procedure enabled comparison of individual plaque status at different time points and the identification of new plaques that had developed over the incubation time. Detailed analysis of the new and pre-existing plaques revealed two key results. Firstly, that new plaques are more likely to form very close (< 40 µm) to a pre-existing plaque than at further distances. New plaques depositing very close to other plaques formed clusters of plaques in the tissue. Secondly, that clusters of close plaques can fuse over time to form a single large plaque. These two key results provide compelling evidence for a clustering hypothesis of large plaque formation and growth. Together, these data provide in vivo support for the clustering hypothesis by which clusters of small plaques merge together to form single plaques over time. This work expands our understanding of how plaques form and develop in AD and could inform the understanding of plaque clearance strategies to combat AD pathological changes in the brains of patients.

No description available.

No description available.

The present work examines top-down shielding from distraction in visual attention; that is, under which circumstances can the intentions and goals of an observer counteract the bottom-up salience of irrelevant distractors. Several factors of influence will be considered: First, prior experience with distractors, i.e. did observers previously acquire an effective distractor shielding strategy; second, intra- vs. cross-dimensionality of distractors, i.e. are irrelevant distractors defined in the same feature dimension (e.g., shape, color) as the target or in a different feature dimension; third, time, i.e. how effective is distractor shielding early vs. later in processing; and finally, the incentive for effective distractor shielding.

Abnormalities in social behavior are found in almost all psychiatric disorders, such as anxiety, depression, autism and schizophrenia. Thus, comprehension of the neurobiological basis of social interaction is important to better understand numerous pathologies and improve treatments. Several evidences suggest that an alteration of cannabinoid CB1 receptor function could be involved in the pathophysiology of such disorders. However, the role of CB1 receptor is still unclear and its localization on different neuronal subpopulations may produce distinct outcomes. To dissect the role of CB1 receptor on different neuronal population, male mice were used – knockout mice and their respective control littermates [total deletion (CB1-/-); specific deletion on cortical glutamatergic neurons (GluCB1-/-); on GABAergic neurons of the forebrain (GABACB1-/-); or on dopaminergic D1 receptor expressing neurons (D1CB1-/-)], and wild-type (WT) mice treated with CB1 antagonist/inverse agonist SR141716A (3mg/kg). To elucidate the behavioral effects of specific CB1 receptor deficiency, D1CB1-/- mice were submitted to a battery of behavioral tests which included exploration-based tests, depressive-like behavioral tests, and fear-related memory paradigms. It was demonstrated that D1CB1-/- mice exhibited significantly increased contextual and auditory-cued fear, with attenuated within-session extinction. Also, when all mice lines were submitted to different social tasks, involving male or female as the stimulus subject, GluCB1-/- mice showed reduced interest for the social stimulus, as CB1-/- or WT treated with SR141716A mice. D1CB1-/- showed moderate changes in social interest, and GABACB1-/- mice showed the opposite phenotype by spending more time investigating the social stimulus. In conclusion, specific reduction of endocannabinoid signaling in D1-expressing neurons is able to affect acute fear adaptation. Moreover, CB1 receptors specifically modulate social investigation of female mice in a cell-specific manner. These findings support the involvement of cannabinoid signaling in social alterations in psychiatry disorders.