Neuro-computational models allow to study the brain mechanisms involved in intelligent behavior and extract essential computational principles which can be implemented in cognitive systems. They are a promising solution to achieve a brain-like artificial intelligence that can compete with natural intelligence on realistic behaviors. A crucial property of intelligent behavior is motivation, defined as the incentive to interact with the world in order to achieve specific goals, either extrinsic (obtaining rewards such as food or money, or avoiding pain) or intrinsic (satisfying one’s curiosity, fun). In the human brain, motivated or goal-directed behavior depends on a network of different structures, including the prefrontal cortex, the basal ganglia and the limbic system. Dopamine, a neurotransmitter associated with reward processing, plays a central role in coordinating the activity of this network. It structures processing in high-level cognitive areas along a limbic-associative-motor gradient and impacts the learning capabilities of the whole system. In this habilitation thesis, I present biologically-constrained neuro-computational models which investigate the role of dopamine in visual object categorization and memory retrieval (Vitay and Hamker, 2008), reinforcement learning and action selection (Vitay and Hamker, 2010), the updating, learning and maintenance of working memory (Schroll et al., 2012) and timing processes (Vitay and Hamker, 2014). These models outline the many mechanisms by which the dopaminergic system regulates cognitive and emotional behavior: bistable processing modes in the cerebral cortex, modulation of synaptic transmission and plasticity, allocation of cognitive resources and signaling of relevant events. Finally, I present a neural simulator able to simulate a variety of neuro-computational models efficiently on parallel architectures (Vitay et al., 2015). / Neuronale Modelle nach dem Vorbild des Gehirns bieten die Möglichkeit intelligente, kognitive Prozesse nicht nur besser zu verstehen, sondern sie stellen auch eine vielversprechende Lösung dar, um eine Gehirn-ähnliche künstliche Intelligenz für Wahrnehmung und Verhaltensweisen zu erreichen, die mit natürlicher Intelligenz konkurrieren kann. Eine entscheidende Eigenschaft von intelligentem Verhalten ist Motivation, definiert als der Anreiz mit der Welt zu interagieren, um bestimmte Ziele zu erreichen, sei es extrinsisch (Belohnungen wie Nahrung oder Geld zu erhalten oder die Vermeidung von Schmerzen) oder intrinsisch (die Neugier zu befriedigen, Spaß zu haben). Im menschlichen Gehirn basiert motiviertes oder zielgerichtetes Verhalten auf einem Netzwerk von verschiedenen Strukturen, einschließlich des präfrontalen Cortex, der Basalganglien und des limbischen Systems. Dopamin, ein Neurotransmitter, welcher der Belohnungsverarbeitung zugeordnet wird, spielt eine zentrale Rolle bei der Koordination der Aktivität in diesem Netzwerk. Es strukturiert die Verarbeitung in High-Level-kognitiven Bereichen entlang eines limbischen-assoziativ-motor Gradienten und beinflusst die Lernfähigkeit des gesamten Systems. In dieser Habilitation, präsentiere ich biologisch motivierte neuronale Modelle, die die Rolle von Dopamin in der visuellen Objektkategorisierung und Gedächtnisabruf (Vitay and Hamker, 2008), Reinforcement Lernen und Aktionsauswahl (Vitay and Hamker, 2010), Aktualisierung, Lernen und Aufrechterhaltung von Arbeitsgedächtnis (Schroll et al., 2012) und Timing Prozessen (Vitay and Hamker, 2014) untersuchen. Diese Modelle beschreiben Mechanismen, durch die das dopaminerge System kognitives und emotionales Verhalten reguliert: bistabile Verarbeitungsmodi in der Hirnrinde, Plastizität und Modulation der synaptischen Übertragung, Zuweisung von kognitiven Ressourcen und Signalisierung von relevanten Ereignissen. Schließlich beschreibe ich einen neuronalen Simulator, der in in der Lage ist, eine Vielzahl von neuronalen Modellen effizient auf parallelen Architekturen zu simulieren (Vitay et al., 2015).

The Aristolochiaceae are one of the largest angiosperm families, the family has been divided into two subfamilies: Asaroideae, which include Asarum and Saruma, and Aristolochioideae, which includes Thottea sensu lato and Aristolochia sensu lato (Kelly and Gonzales, 2003). Aristolochia sensu lato comprise between 450 and 600 species, distributed throughout the world with centers of diversities in the tropical and subtropical regions (Neinhuis et al., 2005, Wanke et al., 2006a, 2007). However, the extended Mediterranean region including Turkey, the Caucasus and the Near East is likely to be the only diversity hotspot of the genus Aristolochia in the northern hemisphere were up to 60 species and subspecies could be observed (Wanke 2007). Most important contributions to the knowledge of these species were published by Nardi (1984, 1988, 1991, 1993) and Davis & Khan (1961, 1964, 1982), all of these studies were based on morphological characters only. In recent years, with the progress of molecular techniques and in light of the systematic chaos, a detailed study was needed to unravel the evolutionary history prior to a taxonomic revision of this group. The first chapter of my thesis should be regarded as the starting point for more detailed investigation on population level. Preliminary molecular phylogenitic analysis recovered the Mediterranean Aristolochia species as monophyletic (de Groot et al 2006). However, only very few members were included in that study. The latest phylogenetic study by Wanke (2007) dealed with west Mediterranean Aristolochia species and sampled also few members belonging to the east Mediterranean and Caucasian species (3 from Greece, 2 from Georgia and 1 from Turkey). This study reported the Mediterranean Aristolochia species as two molecular and morphologically well supported clades, which were sister to each other. Furthermore, the two closely related species A. sempervirens and A. baetica which have an east west vicariance and are known as Aristolochia sempervirens complex has been recovered as sister group to the remaining west Mediterranean species. A detailed investigation of the evolutionary history of this group is the topic of the second chapter of my thesis (Chapter 2). The Aristolochia sempervirens complex is characterized by an unusual growth form and has a circum Mediterranean distribution. The investigation of these species complex seem to be of great importance to understand speciation and colonization of the Mediterranean by the genus Aristolochia and might shade light in historical evolutionary processes of other plant lineages in the Mediterranean. Furthermore, I test applicability and phylogenetic power of a nuclear single copy gene (nSCG) region to reconstruct well resolved and highly supported gene genealogies as a prerequisite to study evolutionary biology questions in general. Furthermore, a comprehensive overview of leaf epicuticular waxes, hairs and trichomes of 54 species from the old and new world taxa of the genus Aristolochia were investigated using scanning electron microscopy (SEM) to clarify taxonomic status of theses species in contrast to their molecular position. Also this study which is the third chapter of this thesis (Chapter 3), has a strong focus on Mediterranean Aristolochia and tries to provide additional support for molecular findings based on epicuticular waxes and to test them as synapomorphies. Each chapter has its own introduction and abstract resulting in a short general introduction here.

Human activities are changing wildfire regimes globally through ignition, spread of invasive species, fire suppression, and climate change. Because of this, ecosystems are experiencing novel fire regimes that may alter plant growth and patterns of succession. Annual growth rings are one metric that can track changes in tree and shrub growth patterns over time in response to changing fire frequency. In Chapter 1 we explored the effects of fire on resprouting native shrubs in the Mojave Desert. Fires are becoming increasingly frequent due to the spread of highly flammable invasive grasses in the region. We monitored growth and fruit production of Larrea tridentata D.C. (creosote bush) on burned and unburned transects from three independent 2005 wildfires. Even though creosote has a high fire mortality rate, we found that resprouting creosote produced 4.7 times the amount of fruit and had stems that grew nearly twice as fast compared to creosote in unburned areas. Our data suggest that creosote can resprout after fire and thrives in its growth rates and reproduction in post-fire environments. In Chapter 2 we used annual Basal Area Increment to investigate how fire suppression has altered facilitation and competition interactions through stages of succession in mixed aspen-conifer forests. We found that aspen had lower growth rates in mixed aspen-conifer stands compared to aspen dominant stands. We also found that aspen growing with an associated fir tree due to facilitation had increasingly lower growth rates over time than those growing independently. Fir trees in mixed stands were facilitated over time by associated aspen trees while fir trees growing in association and independently in aspen stands showed no statistical difference from each other but grew better than independent fir trees in mixed stands. Our data suggest that restoring a more frequent fire regime will balance competitive interactions between aspen and conifer in subalpine forests.

Das Basalzellkarzinom (BZK) der Haut gilt als einer der häufigsten semimalignen Tumoren. Trotz der niedrigen Metastasierungsrate von < 0,1 % können BZK schwerwiegende Infiltrationen und Destruktionen knorpeliger sowie knöcherner Strukturen verursachen. Für die Tumorentstehung ist vor allem die kumulative UVB-Dosis in Kindheit und Adoleszenz bedeutsam. Aber auch die Embryonalentwicklung scheint eine Rolle in der Pathogenese von Tumoren zu spielen. Die so genannte embryonale Fusionszone (eFZ) entsteht zwischen der 5-10 Entwicklungswoche durch die Verschmelzung der fünf Gesichtswülste. Es konnte gezeigt werden, dass BZK innerhalb dieses Kompartiments nicht nur gehäuft auftreten sondern auch durch ein ausgeprägtes Tiefenwachstum charakterisiert sind. Als mögliche Ursache für das verstärkt invasive Wachstum von BZK innerhalb der eFZ wurden Änderungen im Hyaluronsäure (HA)-Stoffwechsel der Stromazellen angenommen. Neben der Bedeutung in der Embryonalentwicklung und bei der Geweberegeneration zeigten verschiedene Studien zudem die essentielle Rolle von HA im Rahmen von malignen Zelltransformationen. Vermehrte HA-Ablagerungen in der Tumorumgebung oder erhöhte HA-Serumkonzentrationen wurden bei einer Vielzahl von Tumoren als Zeichen einer fortschreitenden Tumorprogression beschrieben. Um den HA-Stoffwechsel von Stromafibroblasten um BZK gezielt zu untersuchen, wurden der HA-Gehalt, die HA-Größe und die exprimierten Enzyme des HA-Stoffwechsels in Abhängigkeit von ihrer Lokalisationen miteinander verglichen. Dabei zeigte sich, dass sowohl innerhalb als auch außerhalb der eFZ vergleichbare Mengen und Polymergrößen von HA sezerniert werden. Molekularbiologische Untersuchungen an expandierten Fibroblasten aus Biopsien verschiedener Lokalisationen zeigten ebenfalls keine Unterschiede in der Expression von mRNA der HA Stoffwechselenzyme nach Herkunft der Fibroblasten. Somit wird geschlussfolgert, dass HA zwar auch im Stroma von BZK gebildet wird, der HA-Stoffwechsel von Stromafibroblasten jedoch kein Merkmal ist, das mit dem vermehrten Auftreten und invasiven Wachstum von BZK im Bereich der embryonalen Fusionszone des Mittelgesichts korreliert.

Intrastriatal injections of L-Pyroglutamate (L-PGA) in mice produced behavioral and neuropathological effects that resemble in part the kainate-injected rat striatal model of Huntington's Disease (HD). The behavioral responses induced after unilateral injections of L-PGA included circling, postural asymmetry of head and trunk and possible dyskinesias. The neuropil in the injected striatum contained dilated profiles, degenerating neurons and oligodendroglia, and numerous phagocytic microglial-like cells. A dose response relation existed. The size of the lesion (expressed as a percent volume of the striatum destroyed) ranged from 1±0.18% at 0.02 μmoles to 20.2±3.97% at 200 μmoles L-PGA (pH=7.3). L-PGA is a weak neurotoxin when compared to kainic acid. Several factors raise interest in the possible role of L-PGA in HD, including the recently reported elevated plasma levels of L-PGA in some HD patients [51,52], and these are considered in the discussion.

In assessing and assimilating the neurodevelopmental basis of the so-called movement disorders it is probably useful to establish certain concepts that will modulate both the variation and selection of affliction, mechanisms-processes and diversity of disease states. Both genetic, developmental and degenerative aberrations are to be encompassed within such an approach, as well as all deviations from the necessary components of behaviour that are generally understood to incorporate "normal" functioning. In the present treatise, both conditions of hyperactivity/hypoactivity, akinesia and bradykinesia together with a constellation of other symptoms and syndromes are considered in conjunction with the neuropharmacological and brain morphological alterations that may or may not accompany them, e.g. following neonatal denervation. As a case in point, the neuroanatomical and neurochemical points of interaction in Attention Deficit and Hyperactivity disorder (ADHD) are examined with reference to both the perinatal metallic and organic environment and genetic backgrounds. The role of apoptosis, as opposed to necrosis, in cell death during grain development necessitates careful considerations of the current explosion of evidence for brain nerve growth factors, neurotrophins and cytokines, and the processes regulating their appearance, release and fate. Some of these processes may posses putative inherited characteristics, like asynuclein, others may to greater or lesser extents be endogenous or semi-endogenous (in food), like the tetrahydroisoquinolines, others exogenous until inhaled or injested through environmental accident, like heavy metals, e.g. mercury. Another central concept of neurodevelopment is cellular plasticity, thereby underlining the essential involvement of glutamate systems and N-methyl-D-aspartate receptor configurations. Finally, an essential assimilation of brain development in disease must delineate the relative merits of inherited as opposed to environmental risks not only for the commonly-regarded movement disorders, like Parkinson's disease, Huntington's disease and epilepsy, but also for afflictions bearing strong elements of psychosocial tragedy, like ADHD, autism and Savantism.

No description available.

Decision-making is comprised of an incredibly varied set of behaviours. However, all vertebrates tend to repeat previously rewarding actions and avoid those that have led to loss, behaviours known collectively as the win-stay, lose-shift strategy. This response strategy is supported by the sensorimotor striatum and nucleus accumbens, structures also implicated in spatial processing and the integration of sensory information in order to guide motor action. Therefore, choices may be represented as spatial-motor actions whose value is determined by the rewards and punishments associated with that action. In this dissertation I demonstrate that the location of choices relative to previous rewards and punishments, rather than their identities, determines their value. Chapters 2 and 4 demonstrate that the location of rewards and punishments drives future decisions to win-stay or lose-shift towards that location. Even when choices differ in colour or shape, choice value is determined by location, not visual identity. Chapter 3 compares decision-making when two, six, twelve, or eighteen choices are present, finding that the value of a win or loss is not tied to a single location, but is distributed throughout the choice environment. Finally, Chapter 5 provides anatomical support for the spatial-motor basis of choice. Specifically, win-stay responses are associated with greater oscillatory activity than win-shift responses in the motor cortex corresponding to the hand used to make a choice, whereas lose-shift responses are accompanied by greater activation of frontal systems compared to lose-stay responses. The win-stay and lose-shift behaviours activate structures known to project to different regions of the striatum. Overall, this dissertation provides behavioural evidence that choice location, not visual identity, determines choice value. / Thesis / Doctor of Philosophy (PhD)

Long-term potentiation (LTP) and depression (LTD) are activity dependent long-lasting changes in synaptic efficacy and have been proposed as mechanisms for learning and memory. Although the exact relationship of LTP and LTD to memory is not known, they do share some properties and mechanisms that relate to memory, such as the strengthening and weakening of synapses. LTP and LTD have been studied extensively in hippocampal brain-slice preparations, due to its relatively organized structure, ease of induction, and its critical function in memory storage. Less work has been done in the neocortex despite the belief that it is heavily involved in the storage of long-term memories. Activity dependent plasticity has also been demonstrated in the basal ganglia in vivo and in vitro, but the results have been somewhat inconsistent. The experiments presented in this thesis explore a novel form of neural plasticity in two excitatory pathways (corticostriatal and thalamocortical) of the basal ganglia motor loop in the intact brain in awake, freely behaving rats. In thalamocortical slice preparations, simultaneous presynaptic stimulation and postsynaptic depolarization can induce L TP in animals prior to the critical period. However the results presented in this thesis show that applied stimulation to the thalamocortical pathway failed to produce either LTP or LTD in the awake freely moving animal.Corticostriatal LTD has been shown in slice preparations following direct tetanic stimulation of the striatum. In the current experiment, cortical stimulation failed to induce LTD although there was an observable decrease in the evoked potential following low-frequency stimulation. Corticostriatal L TP has been shown to depend on the type of stimulation applied. High-frequency and theta burst stimulation produced long-lasting changes in response amplitude in the corticostriatal pathway, with theta burst stimulation appearing to be the more effective stimulation protocol for inducing LTP in both the early and late components. Paired stimulation of the substantia nigra pars compacta and cortex indicated a modulatory action of dopamine on corticostriatal synaptic plasticity. Pairing led to a stable increase in the amplitude of LTP of both early and late components. We also report that a temporal relationship exists in the striatum with respect to the release of nigral dopamine and cortical glutamate. Simultaneous stimulation produced a more robust L TP compared to the two other conditions in which there was an applied stimulation delay to either the corticostriatal or nigrostriatal pathway. The results demonstrate the mechanistic differences, not only between the thalamocortical and corticostriatal pathways, but also slice and anesthetized preparations. The results also emphasize the need for further study on mechanisms of L TP and LTD in the various excitatory and inhibitory pathways of the basal ganglia motor loop. / Thesis / Doctor of Philosophy (PhD)

Accumulating evidence suggests that dopaminergic neurons show significant task-related diversity. Curiously, dopamine concentration and dopamine axon activity show spatio-temporal wave patterns in the dorsal striatum. What could be the function of this wave-like dynamics of dopamine in the striatum, particularly in Reinforcement Learning? This work introduces a novel Reinforcement Learning algorithm that exploits the wave-like dynamics of dopamine to increase speed, reliability and flexibility in decision-making. An agent can form a cognitive map by exploring the environment and obtaining the information about the expectation of time spent in each future state given a departing state (i.e. the Successor Representation). This map captures the temporal connections of the visited states and outlines several possible state transition trajectories leading to the reward. Using the cognitive map, following a single reward delivery, the reward prediction errors can be computed for each state. In the cognitive map, states leading to the reward possess a high positive error, while temporally distant states retain smaller errors. Thus, the dynamics of errors exhibit a wave front travelling in the cognitive map. Under the assumption of the neurons representing adjacent states in the cognitive map are also spatial neighbors, it automatically follows that the reward prediction error carrying signal will also show wave-like dynamics in space. By exploiting the dopamine waves, the proposed Reinforcement Learning approach outperforms three classical Reinforcement Learning algorithms: basic SARSA, the Successor Representation and SARSA with eligibility traces. Consequently, the algorithm suggests conditions under which wave-like dynamics of dopamine release in the striatum can have direct functional implications for learning. / En ökande mängd bevis pekar på att dopaminerga nervceller uppvisar en betydande uppgiftsrelaterad diversitet. Märkligt nog uppvisar såväl dopaminkoncentrationen som aktiviteten i dopaminerga axon i dorsala striatum en vågliknande dynamik. Vilken funktion kan dopaminets vågliknande dynamik tänkas fylla i striatum, särskillt vid förstärkningsinlärning? I detta arbete introduceras en ny förstärkningsinlärningsalgoritm som utnyttjar dopaminets vågliknande dynamik för att öka snabbheten, tillförlitligheten och flexbiliteten vid beslutsfattande. En agent kan skapa en kognitiv karta genom att utforska en miljö och tillgodogöra sig information om den förväntade tiden som kommer tillbringas i varje framtida tillstånd givet ett starttillstånd (en så kallad successionsrepresentation). Denna karta fångar upp de tidsmässiga förbindelserna mellan besökta tillstånd och ger en skiss för flera möjliga serier av tillståndsövergångar som leder till belöning. Genom att använda denna kognitiva karta efter en enskild belöning kan belöningsförutsägningsfel beräknas för varje tillstånd. I den kognitiva kartan har tillstånd som leder till belöning ett stort positivt fel, medan tidsmässigt avlägsna tillstånd har mindre fel. Detta ger upphov till att dynamiken för felen uppvisar en vågfront in den kognitiva kartan. Under antagandet att nervceller som representerar närliggande tillstånd i den kognitiva kartan också är fysiska grannar, följer det automatiskt att signalen för belöningsförutsägningsfel också uppvisar en våglikannde dynamik i rummet. Genom att utnyttja dopaminvågor överträffar den föreslagna förstärkningsinlärningsalgoritmen tre klassiska förstärkningsinlärningsalgoritmer: vanlig SARSA, successionsrepresentation, och SARSA med kvalificeringsspår. Algoritmen förslår därför betingelser under vilka en vågliknande dynamik av dopaminfrisättning i striatum kan ha direkta funktionella implikationer för inlärning.