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Sonstige beteiligte Institutionen
According to a changing environment it is crucial for animals to make experience and learn about it. Sensing, integrating and learning to associate different kinds of modalities enables animals to expect future events and to adjust behavior in the way, expected as the most profitable. Complex processes as memory formation and storage make it necessary to investigate learning and memory on different levels. In this context Drosophila melanogaster represents a powerful model organism. As the adult brain of the fly is still quite complex, I chose the third instar larva as model - the more simple the system, the easier to isolate single, fundamental principles of learning. In this thesis I addressed several kinds of questions on different mechanism of olfactory associative and synaptic plasiticity in Drosophila larvae. I focused on short-term memory throughout my thesis. First, investigating larval learning on behavioral level, I developed a one-odor paradigm for olfactory associative conditioning. This enables to estimate the learnability of single odors, reduces the complexity of the task and simplify analyses of "learning mutants". It further allows to balance learnability of odors for generalization-type experiments to describe the olfactory "coding space". Furthermore I could show that innate attractiveness and learnability can be dissociated and found finally that paired presentation of a given odor with reward increase performance, whereas unpaired presentations of these two stimuli decrease performance, indicating that larva are able to learn about the presence as well as about the absence of a reward. Second, on behavioral level, together with Thomas Niewalda and colleagues we focussed on salt processing in the context of choice, feeding and learning. Salt is required in several physiological processes, but can neither be synthesized nor stored. Various salt concentrations shift the valence from attraction to repulsion in reflexive behaviour. Interestingly, the reinforcing effect of salt in learning is shifted by more than one order of magnitude toward higher concentrations. Thus, the input pathways for gustatory behavior appear to be more sensitive than the ones supporting gustatory reinforcement, which is may be due to the dissociation of the reflexive and the reinforcing signalling pathways of salt. Third, in cooperation with Michael Schleyer we performed a series of behavioral gustatory, olfactory preference tests and larval learning experiments. Based on the available neuroanatomical and behavioral data we propose a model regarding chemosensory processing, odor-tastant memory trace formation and the 'decision' like process. It incorporates putative sites of interaction between olfactory and gustatory pathways during the establishment as well as behavioral expression of odor-tastant memory. We claim that innate olfactory behavior is responsive in nature and suggest that associative conditioned behavior is not a simple substitution like process, but driven more likely by the expectation of its outcome. Fourth, together with Birgit Michels and colleagues we investigated the cellular site and molecular mode of Synapsin, an evolutionarily conserved, presynaptic vesicular phosphoprotein and its action in larval learning. We confirmed a previously described learning impairment upon loss of Synapsin. We localized this Synapsin dependent memory trace in the mushroom bodies, a third-order "cortical" brain region, and could further show on molecular level, that Synapsin is as a downstream element of the AC-cAMP-PKA signalling cascade. This study provides a comprehensive chain of explanation from the molecular level to an associative behavioral change. Fifth, in the main part of my thesis I focused on molecular level on another synaptic protein, the Synapse associated protein of 47kDa (Sap47) and its role in larval behavior. As a member of a phylogenetically conserved gene family of hitherto unknown function. It is localized throughout the whole neuropil of larval brains and associated with presynaptic vesicles. Upon loss of Sap47 larvae exhibit normal sensory detection of the to-be-associated stimuli as well as normal motor performance and basic synaptic transmission. Interestingly, short-term plasticity is distorted and odorant–tastant associative learning ability is reduced. This defect in associative function could be rescued by restoring Sap47 expression. Therefore, this report is the first to suggest a function for Sap47 and specifically argues that Sap47 is required for synaptic as well as for behavioral plasticity in Drosophila larva. This prompts the question whether its homologs are required for synaptic and behavioral plasticity also in other species. Further in the last part of my thesis I contributed to the study of Ayse Yarali. Her central topic was the role of the White protein in punishment and relief learning in adult flies. Whereas stimuli that precede shock during training are subsequently avoided as predictors for punishment, stimuli that follow shock during training are later on approached, as they predict relief. Concerning the loss of White we report that pain-relief learning as well as punishment learning is changed. My contribution was a comparison between wild type and the white1118 mutant larvae in odor-reward learning. It turned out that a loss of White has no effect on larval odorant-tastant learning. This study, regarding painrelief learning provides the very first hints concerning the genetic determinants of this form of learning.
Epimutations in Germ-Cell and Embryo Development: Possible Consequences for Assisted Reproduction
(2011)
Assisted reproductive technologies (ART) emerged in the late 1970’s as a therapy for human infertility. Up till now more than 3 million babies have been conceived through ART, demonstrating the safety and efficiency of the technique. Published reports showed an increase in the rate of imprinting disorders (Beckwith Wiedemann Syndrome, Angelman Syndrome, etc.) in babies born after ART. What are the effects imposed through ART and should researchers reassess its safety and implications on the future offspring? Throughout this thesis, I analyzed the methylation patterns of germ cells and embryos to determine whether in vitro maturation and in vitro fertilization have a negative impact on the epigenetic patterns. Furthermore, DNA methylation was compared between sperm of infertile and presumably fertile controls in order to understand whether epigenetic disturbances lead to infertility at the first place. The occurrence of methylation aberrations in germ cells of infertile patients could be transmitted to new-borns and then cause epigenetic disorders. In order to elucidate the imprinting status within single cells, I developed a new technique based on limiting dilution where bisulfite treated DNA is distributed across several wells before amplification. This allowed methylation measurement at the single allele level as well parent of origin detection. In a total of 141 sperm samples from couples undergoing in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) including 106 with male factor or combined infertility and 28 with female infertility, I detected a significant correlation between lower quality of semen parameters (sperm count, percentage of abnormal sperm, and percentage of motile sperm) and the rate of imprinting errors. ALU repeats displayed a higher methylation in sperm DNA of patients leading to a pregnancy and live birth, compared to patients in which pregnancy was not achieved or a spontaneous abortion occurred. A discriminant analysis based on ALU methylation allowed correct classification of >70% of cases. Preliminary data from illumina methylation arrays where more than 27,000 CpGs were analyzed determined that only a single CpG site from the open reading frame C14orf93 was significantly different between the infertile and presumably fertile control group. However, further improvements on data normalization might permit detection of other differentially methylated regions. Comparison of embryos after natural conception, in vitro fertilized embryos from superovulated oocytes, and embryos achieved through fertilization of in vitro cultured oocytes revealed no dramatic effect on the imprinting patterns of Igf2r, H19, and Snrpn. Oocyte cryotop vitrification did not result in a dramatic increase of imprinting mutations in oocytes even though the rate of sporadic methylation errors in single Snrpn CpGs were higher within the in-vitrified group. Collectively, the results I will present within this thesis suggest an increase in the rate of imprinting errors within the germ cells of infertile patients, in addition to a decrease in genome wide methylation of ALU repetitive elements. I did not observe a detrimental effect on the methylation patterns of oocytes and the resulting embryos using in vitro maturation of oocytes and/or standard IVF with in vivo grown superovulated oocytes.
The present work investigated the neural mechanisms underlying cognitive inhibition/thought suppression in Anderson’s and Green’s Think/No-Think paradigm (TNT), as well as different variables influencing these mechanisms at the cognitive, the neurophysiological, the electrophysiological and the molecular level. Neurophysiological data collected with fNIRS and fMRI have added up to the existing evidence of a fronto-hippocampal network interacting during the inhibition of unwanted thoughts. Some evidence has been presented suggesting that by means of external stimulation of the right dlPFC through iTBS thought suppression might be improved, providing further evidence for an implication of this region in the TNT. A combination of fNIRS with ERP has delivered evidence of a dissociation of early condition-independent attentional and later suppression-specific processes within the dlPFC, both contributing to suppression performance. Due to inconsistencies in the previous literature it was considered how stimulus valence would influence thought suppression by manipulating the emotional content of the to-be-suppressed stimuli. Findings of the current work regarding the ability to suppress negative word or picture stimuli have, however, been inconclusive as well. It has been hypothesized that performance in the TNT might depend on the combination of valence conditions included in the paradigm. Alternatively, it has been suggested that inconsistent findings regarding the suppression of negative stimuli or suppression at all might be due to certain personality traits and/or genetic variables, found in the present work to contribute to thought inhibition in the TNT. Rumination has been shown to be a valid predictor of thought suppression performance. Increased ruminative tendencies led to worse suppression performance which, in the present work, has been linked to less effective recruitment of the dlPFC and in turn less effective down-regulation of hippocampal activity during suppression trials. Trait anxiety has also been shown to interrupt thought suppression despite higher, however, inefficient recruitment of the dlPFC. Complementing the findings regarding ruminative tendencies and decreased thought inhibition a functional polymorphism in the KCNJ6 gene, encompassing a G-to-A transition, has been shown to disrupt thought suppression despite increased activation of the dlPFC. Through the investigation of thought suppression at different levels, the current work adds further evidence to the idea that the TNT reflects an executive control mechanism, which is sensitive to alterations in stimulus valence to some extent, neurophysiological functioning as indicated by its sensitivity to iTBS, functional modulations at the molecular level and personality traits, such as rumination and trait anxiety.
In this thesis a systematic analysis of the correlation effects between lattice dynamics and magnetism in the Multiferroic Manganites RMnO3 with Pnma structure was conducted. For this task, Raman and FT-IR Spectroscopy were employed for an investigation of all optically accessible lattice vibrations, i.e. phonons. To study the correlation effects as well as their specific connections to symmetry and compositional properties of the Multiferroic Manganites, the polarisation and temperature dependence of the phonons were considered explicitly. In combination with lattice dynamical calculations based on Density Functional Theory, two coupling effects - Spin-Phonon Coupling and Electromagnon-Phonon Coupling - were systematically analysed.
Honeybees (Apis mellifera) forage on a great variety of plant species, navigate over large distances to crucial resources, and return to communicate the locations of food sources and potential new nest sites to nest mates using a symbolic dance language. In order to achieve this, honeybees have evolved a rich repertoire of adaptive behaviours, some of which were earlier believed to be restricted to vertebrates. In this thesis, I explore the mechanisms involved in honeybee learning, memory, numerical competence and navigation. The findings acquired in this thesis show that honeybees are not the simple reflex automats they were once believed to be. The level of sophistication I found in the bees’ memory, their learning ability, their time sense, their numerical competence and their navigational abilities are surprisingly similar to the results obtained in comparable experiments with vertebrates. Thus, we should reconsider the notion that a bigger brain automatically indicates higher intelligence.
Attention-deficit/hyperactivity disorder (ADHD) is a genetically complex childhood onset neurodevelopmental disorder which is highly persistent into adulthood. Several chromo-somal regions associated with this disorder were identified previously in genome-wide linkage scans, association (GWA) and copy number variation (CNV) studies. In this work the results of case-control and family-based association studies using a can-didate gene approach are presented. For this purpose, possible candidate genes for ADHD have been finemapped using mass array-based SNP genotyping. The genes KCNIP4, CDH13 and DIRAS2 have been found to be associated with ADHD and, in addition, with cluster B and cluster C personality disorders (PD) which are known to be related to ADHD. Most of the associations found in this work would not withstand correction for multiple testing. However, a replication in several independent populations has been achieved and in conjunction with previous evidence from linkage, GWA and CNV studies, it is assumed that there are true associations between those genes and ADHD. Further investigation of DIRAS2 by quantitative real-time PCR (qPCR) revealed expression in the hippocampus, cerebral cortex and cerebellum of the human brain and a significant increase in Diras2 expression in the mouse brain during early development. In situ hybrid-izations on murine brain slices confirmed the results gained by qPCR in the human brain. Moreover, Diras2 is expressed in the basolateral amygdala, structures of the olfactory system and several other brain regions which have been implicated in the psychopatholo-gy of ADHD. In conclusion, the results of this work provide further support to the existence of a strong genetic component in the pathophysiology of ADHD and related disorders. KCNIP4, CDH13 and DIRAS2 are promising candidates and need to be further examined to get more knowledge about the neurobiological basis of this common disease. This knowledge is essential for understanding the molecular mechanisms underlying the emergence of this disorder and for the development of new treatment strategies.
During the last decades the standard model of particle physics has evolved to one of the most precise theories in physics, describing the properties and interactions of fundamental particles in various experiments with a high accuracy. However it lacks on some shortcomings from experimental as well as from theoretical point of view: There is no approved mechanism for the generation of masses of the fundamental particles, in particular also not for the light, but massive neutrinos. In addition the standard model does not provide an explanation for the observance of dark matter in the universe. Moreover the gauge couplings of the three forces in the standard model do not unify, implying that a fundamental theory combining all forces can not be formulated. Within this thesis we address supersymmetric models as answers to these various questions, but instead of focusing on the most simple supersymmetrization of the standard model, we consider basic extensions, namely the next-to-minimal supersymmetric standard model (NMSSM), which contains an additional singlet field, and R-parity violating models. R-parity is a discrete symmetry introduced to guarantee the stability of the proton. Using lepton number violating terms in the context of bilinear R-parity violation and the munuSSM we are able to explain neutrino physics intrinsically supersymmetric, since those terms induce a mixing between the neutralinos and the neutrinos. Since 2009 the Large Hadron Collider (LHC) at CERN explores the new energy regime of Tera-electronvolt, allowing the production of potentially existing heavy particles by the collision of protons. Thus the near future might provide answers to the open questions of mass generation in the standard model and show hints towards physics beyond the standard model. Therefore this thesis works out the phenomenology of the supersymmetric models under consideration and tries to point out differences to the well-known features of the simplest supersymmetric realization of the standard model. In case of the R-parity violating models the decays of the light neutralinos can result in displaced vertices. In combination with a light singlet state these displaced vertices might offer a rich phenomenology like non-standard Higgs decays into a pair of singlinos decaying with displaced vertices. Within this thesis we present some calculations at next order of perturbation theory, since one-loop corrections provide possibly large contributions to the tree-level masses and decay widths. We are using an on-shell renormalization scheme to calculate the masses of neutralinos and charginos including the neutrinos and leptons in case of the R-parity violating models at one-loop level. The discussion shows the similarities and differences to existing calculations in another renormalization scheme, namely the DRbar scheme. Moreover we consider two-body decays of the form chi_j^0 -> chi_l^\pm W^\mp involving a heavy gauge boson in the final state at one-loop level. Corrections are found to be large in case of small or vanishing tree-level decay widths and also for the R-parity violating decay of the lightest neutralino chi_1^0 -> l^\pm W^\mp. An interesting feature of the models based on bilinear R-parity violation is the correlation between the branching ratios of the lightest neutralino decays and the neutrino mixing angles. We discuss these relations at tree-level and for two-body decays chi_1^0 -> l^\pm W^\mp also at one-loop level, since only the full one-loop corrections result in the tree-level expected behavior. The appendix describes the two programs MaCoR and CNNDecays being developed for the analysis carried out in this thesis. MaCoR allows for the calculation of mass matrices and couplings in the models under consideration and CNNDecays is used for the one-loop calculations of neutralino and chargino mass matrices and the two-body decay widths.
Indirect Search for Dark Matter in the Universe - the Multiwavelength and Multiobject Approach
(2011)
Cold dark matter constitutes a basic tenet of modern cosmology, essential for our understanding of structure formation in the Universe. Since its first discovery by means of spectroscopic observations of the dynamics of the Coma cluster some 80 years ago, mounting evidence of its gravitational pull and its impact on the geometry of space-time has build up across a wide range of scales, from galaxies to the entire Hubble flow. The apparent lack of electromagnetic coupling and independent measurements of the energy density of baryonic matter from the primordial abundances of light elements show the non-baryonic nature of dark matter, and its clustering properties prove that it is cold, i.e. that it has a temperature lower than its mass during the time of radiation-matter equality. A generic particle candidate for cold dark matter are weakly interacting massive particles at the electroweak symmetry-breaking scale, such as the neutralinos in R-parity conserving supersymmetry. Such particles would naturally freeze-out with a cosmologically relevant relic density at early times in the expanding Universe. Subsequent clustering of matter would recover annihilation interactions between the dark matter particles to some extent and thus lead to potentially observable high-energy emission from the decaying unstable secondaries produced in annihilation events. The spectra of the secondaries would permit a determination of the mass and annihilation cross section, which are crucial for the microphysical identification of the dark matter. This the central motivation for indirect dark matter searches. However, presently neither the indirect searches, nor the complementary direct searches based on the detection of elastic scattering events, nor the production of candidate particles in collider experiments, has yet provided unequivocal evidence for dark matter. This does not come as a surprise, since the dark matter particles interact only through weak interactions and therefore the corresponding secondary emission must be extremely faint. It turns out that even for the strongest mass concentrations in the Universe, the dark matter annihilation signal is expected to not exceed the level of competing astrophysical sources. Thus, the discrimination of the putative dark matter annihilation signal from the signals of the astrophysical inventory has become crucial for indirect search strategies. In this thesis, a novel search strategy will be developed and exemplified in which target selection across a wide range of masses, astrophysical background estimation, and multiwavelength signatures play the key role. It turns out that the uncertainties regarding the halo profile and the boost due to surviving substructure are bigger for halos at the lower end of the observed mass scales, i.e. in the regime of dwarf galaxies and below, while astrophysical backgrounds tend to become more severe for massive dark matter halos such as clusters of galaxies. By contrast, the uncertainties due to unknown details of particle physics are invariant under changes of the halo mass. Therefore, the different scaling behaviors can be employed to significantly cut down on the uncertainties in observations of different targets covering a major part of the involved mass scales. This strategical approach was implemented in the scientific program carried out with the MAGIC telescope system. Observations of dwarf galaxies and the Virgo- and Perseus clusters of galaxies have been carried out and, at the time of writing, result in some of the most stringent constraints on weakly interacting massive particles from indirect searches. Here, the low-threshold design of the MAGIC telescope system plays a crucial role, since the bulk of the high-energy photons, produced with a high multiplicity during the fragmentation of unstable dark matter annihilation products, are emitted at energies well below the dark matter mass scale. The upper limits severely constrain less generic, but more prolific scenarios characterized by extraordinarily high annihilation efficiencies.
The subject of this thesis are mathematical programs with complementarity conditions (MPCC). At first, an economic example of this problem class is analyzed, the problem of effort maximization in asymmetric n-person contest games. While an analytical solution for this special problem could be derived, this is not possible in general for MPCCs. Therefore, optimality conditions which might be used for numerical approaches where considered next. More precisely, a Fritz-John result for MPCCs with stronger properties than those known so far was derived together with some new constraint qualifications and subsequently used to prove an exact penalty result. Finally, to solve MPCCs numerically, the so called relaxation approach was used. Besides improving the results for existing relaxation methods, a new relaxation with strong convergence properties was suggested and a numerical comparison of all methods based on the MacMPEC collection conducted.
The charge transport in disordered organic bulk heterojunction (BHJ) solar cells is a crucial process affecting the power conversion efficiency (PCE) of the solar cell. With the need of synthesizing new materials for improving the power conversion efficiency of those cells it is important to study not only the photophysical but also the electrical properties of the new material classes. Thereby, the experimental techniques need to be applicable to operating solar cells. In this work, the conventional methods of transient photoconductivity (also known as "Time-of-Flight" (TOF)), as well as the transient charge extraction technique of "Charge Carrier Extraction by Linearly Increasing Voltage" (CELIV) are performed on different organic blend compositions. Especially with the latter it is feasible to study the dynamics, i.e. charge transport and charge carrier recombination, in bulk heterojunction (BHJ) solar cells with active layer thicknesses of 100-200 nm. For a well performing organic BHJ solar cells the morphology is the most crucial parameter finding a trade-off between an efficient photogeneration of charge carriers and the transport of the latter to the electrodes. Besides the morphology, the nature of energetic disorder of the active material blend and its influence on the dynamics are discussed extensively in this work. Thereby, the material system of poly(3-hexylthiophene-2,5-diyl) (P3HT) and [6,6]-phenyl-C61 butyric acid methyl ester (PC61BM) serves mainly as a reference material system. New promising donor or acceptor materials and their potential for application in organic photovoltaics are studied in view of charge dynamics and compared with the reference system. With the need for commercialization of organic solar cells the question of the impact of environmental conditions on the PCE of the solar cells raises. In this work, organic BHJ solar cells exposed to synthetic air for finite duration are studied in view of the charge carrier transport and recombination dynamics. Finally, within the framework of this work the technique of photo-CELIV is improved. With the modified technique it is now feasible to study the mobility and lifetime of charge carriers in organic solar cells under operating conditions.